Octahydropentalene compounds as chemokine receptor antagonists

ABSTRACT

The present invention is directed to novel compounds of Formula (I) 
                         
pharmaceutically acceptable salts thereof, pro-drugs thereof, biologically active metabolites thereof, isomers thereof or stereoisomers thereof wherein the variables are as defined herein. The compounds of Formula (I) are useful as chemokine receptor antagonists and as such would be useful in treating certain conditions and diseases, especially inflammatory conditions and diseases and proliferative disorders and conditions, for example, rheumatoid arthritis, osteoarthritis, multiple sclerosis and asthma.

CROSS REFERENCE TO RELATED APPLICATION

This application is a divisional of U.S. application Ser. No. 12/284,758filed on Sep. 25, 2008, which claims priority to U.S. ProvisionalApplication Ser. No. 60/995,148 filed on Sep. 25, 2007, the contents ofwhich are incorporated herein.

BACKGROUND OF THE INVENTION

Chemokines are chemotactic cytokines that are released by a wide varietyof cells to attract leukocytes, as illustrated by macrophages, T cells,B cells, eosinophils, basophils, and neutrophils to and from sites ofinflammation or within specific compartments, as illustrated by lymphnodes (reviewed in Schall, Cytokine, 3:165-183 (1991), Schall, et al.,Curr. Opin. Immunol., 6:865-873 (1994) and Murphy, Rev. Immun.,12:593-633 (1994)). In addition to stimulating chemotaxis, other changescan be selectively induced by chemokines in responsive cells, includingchanges in cell shape, transient rises in the concentration ofintracellular free calcium ions ([Ca²⁺]), granule exocytosis, integrinupregulation, formation of bioactive lipids (e.g., leukotrienes), andrespiratory burst, associated with leukocyte activation. Thus, thechemokines are early modulators of inflammatory response, effectinginflammatory mediator release, chemotaxis and extravasation to sites ofinfection or inflammation.

There are four classes of chemokines, CXC (α), CC (β), C (γ), and CX₃C(δ), depending on whether the first two cysteines are separated by asingle amino acid (C-X-C), are adjacent (C-C), have a missing cysteinepair (C), or are separated by three amino acids (CX₃C). Theα-chemokines, such as interleukin-8 (IL-8), melanoma growth stimulatoryactivity protein (MGSA), and stromal cell derived factor 1 (SDF-1) arechemotactic primarily for neutrophils and lymphocytes, whereasβ-chemokines, such as RANTES, MIP-1α, MIP-1β, monocyte chemotacticprotein-1 (MCP-1), MCP-2, MCP-3, and eotaxin are chemotactic formacrophages, T-cells, eosinophils and basophils (Deng, et al., Nature,381:661-666 (1996)). The C chemokine lymphotactin shows specificity forlymphocytes (Kelner, et al., Science, 266:1395-1399 (1994)) while theCX₃C chemokine fractalkine shows specificity for lymphocytes andmonocytes (Bazan, et al., Nature, 385:640-644 (1997)).

Chemokines bind specific cell-surface receptors belonging to the familyof G-protein-coupled seven-transmembrane-domain proteins (reviewed inHoruk, Trends Pharm. Sci., 15:159-165 (1994)) termed “chemokinereceptors.” On binding their cognate ligands, chemokine receptorstransduce an intracellular signal through the associated heterotrimericG protein, resulting in a rapid increase in intracellular calciumconcentration. There are at least twelve human chemokine receptors thatbind or respond to β-chemokines with the following characteristicpattern: CCR1 (or “CKR-1” or “CC-CKR-1”) MIP-1α, MIP-1β, MCP-3, RANTES(Ben-Barruch, et al., J. Biol. Chem., 270:22123-22128 (1995); Neote, etal., Cell, 72:415425 (1993)); CCR2A and CCR2B (or “CKR-2A”/“CKR-2A” or“CC-CKR-2A”/“CC-CKR2A”) MCP-1, MCP-2, MCP-3, MCP-4; CCR3 (or “CKR-3” or“CC-CKR-3”) eotaxin, RANTES, MCP; (Ponath, et al., J. Exp. Med.,183:2437-2448 (1996)); CCR4 (or “CKR-4” or “CC-CKR-4”) TARC, MDC (Imai,et al., J. Biol. Chem., 273:1764-1768 (1998)); CCR5 (or “CKR-5” or“CC-CKR-5”) MIP-1α, RANTES, MIP-1β; (Sanson, et al., Biochemistry,35:3362-3367 (1996)); CCR6MIP-3a (Greaves, et al., J. Exp. Med.,186:837-844 (1997)); CCR7MIP-3β and 6Ckine (Campbell, et al., J. Cell.Biol., 141:1053-1059 (1998)); CCR8 I-309, HHV8 vMIP-I, HHV-8 vMIP-II,MCV vMCC-I (Dairaghi, et al., J. Biol. Chem., 274:21569-21574 (1999));CCR9 TECK (Zaballos, et al., J. Immunol., 162:5671-5675 (1999)), D6MIP-1 beta, RANTES, and MCP-3 (Nibbs, et al., J. Biol. Chem.,272:32078-32083 (1997)), and the Duffy blood-group antigen RANTES, MCP-1(Chaudhun, et al., J. Biol. Chem., 269:7835-7838 (1994)).

Chemokine receptors, such as CCR1, CCR2, CCR3, CCR4, CCR5, CCR6, CCR7,CCR8, CCR9, CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CX₃CR1, and XCR1 havebeen implicated as being important mediators of inflammatory andimmunoregulatory disorders and diseases, including asthma and allergicdiseases, as well as autoimmune pathologies such as rheumatoid arthritisand atherosclerosis.

The CCR2 chemokine receptor is expressed primarily in monocytes andactivated T lymphocytes, and its functional activity can be measured bycytosolic calcium elevation or chemotaxis. CCR2 exists in two isoforms,CCR2A and CCR2B. These two isoforms are alternatively spliced variantsof a single MCP-1 receptor gene and differ only in the carboxyl-terminaltails. The chromosomal location of the CCR2 gene is localized to 3p21.Ligands that have been identified that are selective and of highaffinity are the CC chemokines, MCP-1, MCP-2, MCP-3 and MCP-4.

The highly selective expression of CCR2 makes it an ideal target forintervention to interrupt inappropriate monocyte and T cell trafficking.The clinical indications for such intervention are in inflammatorydiseases and T-cell mediated autoimmune diseases such as multiplesclerosis, rheumatoid arthritis, asthma, allergy, chronic obstructivepulmonary disease, atherosclerosis, restinosis, type I and type IIdiabetes, metabolic syndrome and neuropathic pain. Ectopic expression ofMCP-1 and CCR2 in certain tumors indicate that selective antagonists ofCCR2 will have value in tumor immunotherapy, particularly attenuation ofmetastasis.

In view of the clinical importance of CCR2, the identification ofcompounds that modulate CCR2 function represents an attractive avenueinto the development of new therapeutic agents. Such compounds areprovided herein.

SUMMARY OF INVENTION

In a first embodiment the invention provides a compound of Formula (I)

pharmaceutically acceptable salts thereof, pro-drugs thereof,biologically active metabolites thereof or isomers thereof wherein

-   -   R^(a) is H or optionally substituted (C₁-C₆)alkyl;    -   R^(b) is selected from the optionally substituted group        consisting of —(CH₂)_(n)-aryl, —CH(CH₃)-aryl,        —(CH₂)_(n)-aryl-aryl, —(CH₂)_(n)-aryl-heteroaryl,        —(CH₂)_(n)—(C₃-C₈)cycloalkyl, —(CH₂)_(n)-heteroaryl,        —(CH₂)_(n)-heterocyclyl and —(C₃-C₈)cycloalkyl-aryl; or    -   R^(a) and R^(b) are taken together with the nitrogen to form        2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally        substituted piperidinyl or optionally substituted pyrrolidinyl;    -   Y is selected from the optionally substituted group consisting        of 5,6,7,8-tetrahydro[1,6]naphthridinyl,        —NH—(CH₂)_(n)-heterocyclyl wherein the NH is attached to the        carbonyl and -heterocyclyl-aryl wherein the heterocyclyl is        attached to the carbonyl; and    -   n is 0, 1 or 2.

In a second embodiment the invention provides a compound according tothe foregoing embodiment wherein Y is selected from the optionallysubstituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthridinyl,—NH—(CH₂)₂-pyrrolidinyl and -piperazinyl-phenyl.

In a third embodiment the invention provides a compound according to anyof the foregoing embodiments wherein R^(a) is H or methyl.

In a fourth embodiment the invention provides a compound according toany of the foregoing embodiments wherein R^(b) is selected from theoptionally substituted group consisting of —CH₂-phenyl,—CH₂-phenyl-phenyl, —(CH₂)₂-phenyl, —CH(CH₃)-phenyl,—CH₂CH₂-phenyl-phenyl, —CH₂-phenyl-pyrazolyl, phenyl-pyrazolyl, indanyl,—(CH₂)₂-indolyl, 1,2,3,4-tetrahydronaphthyl, —(CH₂)-pyrazinyl,—(CH₂)-pyridinyl, —(CH₂)₂-pyridinyl, —(CH₂)₂-pyrrolidinyl,—(CH₂)₂-thienyl, tetrahydrothienyl-1,1-dioxide, —(CH₂)₂-piperidinyl,tetrahydropyranyl and -cyclohexyl-phenyl.

In a fifth embodiment the invention provides a compound according to anyof the foregoing embodiments wherein R^(b) is selected from theoptionally substituted group consisting of —CH₂-phenyl, —(CH₂)₂-phenyl,—CH₂-phenyl-pyrazolyl, indanyl, —(CH₂)₂-indolyl,1,2,3,4-tetrahydronaphthyl, —(CH₂)₂-pyridinyl and -cyclohexyl-phenyl.

In a sixth embodiment the invention provides a compound according to anyof the foregoing embodiments wherein Y is selected from the optionallysubstituted group consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyland -piperazinyl-phenyl.

In a seventh embodiment the invention provides a compound according toany of the foregoing embodiments wherein R^(b) is selected from theoptionally substituted group consisting of —CH₂-phenyl, —(CH₂)₂-phenyl,1,2,3,4-tetrahydronaphthyl, —CH₂-phenyl-pyrazolyl, indanyl,—(CH₂)₂-pyridinyl and -cyclohexyl-phenyl.

In an eighth embodiment the invention provides a compound according toany of the foregoing embodiments wherein R^(b) is selected from theoptionally substituted group consisting of —CH₂-phenyl,1,2,3,4-tetrahydronapthyl and -cyclohexyl-phenyl.

In a ninth embodiment the invention provides a compound according to anyof the foregoing embodiments wherein R^(b) is optionally substitutedwith one or more substituents selected from the group consisting ofalkyl, alkoxy, halogen, CN, OH, CF₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂.

In a tenth embodiment the invention provides a compound according to anyof the foregoing embodiments wherein Y is optionally substituted withCF₃.

In an eleventh embodiment the invention provides a compound according toany of the foregoing embodiments wherein R^(a) and R^(b) are takentogether with the nitrogen to form 2,3-dihydro-1H-isoindolyl,5,6,7,8-tetrahydro[1,6]naphthyridinyl, optionally substitutedpiperidinyl or optionally substituted pyrrolidinyl.

In a twelfth embodiment the invention provides a compound according tothe eleventh embodiment wherein the optionally substituted piperidinylor optionally substituted pyrrolidinyl is optionally substituted bysubstituents selected from the group consisting of optionallysubstituted cyclohexyl and optionally substituted phenyl.

In a thirteenth embodiment the invention provides a compound accordingto any of the foregoing embodiments wherein Y is optionally substituted5,6,7,8 tetrahydro[1,6]naphthyridinyl.

In a fourteenth embodiment the invention provides a compound accordingto the thirteenth embodiment wherein the optionally substitutedpiperidinyl is substituted with optionally substituted phenyl oroptionally substituted pyrrolidinyl.

In a fifteenth embodiment the invention provides a compound according tofourteenth embodiments wherein the optionally substituted piperidinyl issubstituted with optionally substituted pyrrolidinyl.

In a sixteenth embodiment the invention provides a compound according tothe fourteenth embodiment wherein the optionally substituted piperidinylis substituted with optionally substituted phenyl.

In a seventeenth embodiment the invention provides a compound accordingto twelfth embodiment wherein the optionally substituted pyrrolidinyl issubstituted by optionally substituted cyclohexyl.

In an eighteenth embodiment the invention provides a method of treatinga condition in a patient comprising administering a therapeuticallyeffective amount of a compound of claim 1 or a physiologicallyacceptable salt thereof to said patient, wherein said condition isselected from the group consisting of rheumatoid arthritis,osteoarthritis, asthma, chronic obstructive pulmonary disease, sepsis,psoriasis, psoriatic arthritis, inflammatory bowel disease, Crohn'sdisease, lupus, multiple sclerosis, juvenile chronic arthritis, Lymearthritis, reactive arthritis, septic arthritis, spondyloarthropathy,systemic lupus erythematosus, an ocular condition, a cancer, a solidtumor, fibrosarcoma, osteoma, melanoma, retinoblastoma, arhabdomyosarcoma, glioblastoma, neuroblastoma, teratocarcinoma, ancancers such as lung, breast, stomach, bladder, colon, pancreas,ovarian, prostate and rectal cancer and hematopoietic malignancies(leukemia and lymphoma), Abetalipoprotemia, Acrocyanosis, acute andchronic parasitic or infectious processes, acute leukemia, acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute orchronic bacterial infection, acute pancreatitis, acute renal failure,adenocarcinomas, aerial ectopic beats, AIDS dementia complex,alcohol-induced hepatitis, allergic conjunctivitis, allergic contactdermatitis, allergic rhinitis, alpha-1 antitrypsin deficiency,amyotrophic lateral sclerosis, anemia, angina pectoris, anterior horncell degeneration, anti cd3 therapy, antiphospholipid syndrome,anti-receptor hypersensitivity reactions, hypersensitivity reactions,hyperkinetic movement disorders, hypersensitivity pneumonitis,hypertension, hypokinetic movement disorders, aortic and peripheralaneurysms, hypothalamic-pituitary-adrenal axis evaluation, aorticdissection, arterial hypertension, arteriosclerosis, arteriovenousfistula, ataxia, spinocerebellar degenerations, streptococcal myositis,structural lesions of the cerebellum, Subacute sclerosingpanencephalitis, Syncope, syphilis of the cardiovascular system,systemic anaphylaxis, systemic inflammatory response syndrome, systemiconset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia,thromboangitis obliterans, transplants, trauma/hemorrhage, type IIIhypersensitivity reactions, type IV hypersensitivity, unstable angina,uremia, urosepsis, urticaria, valvular heart diseases, varicose veins,vasculitis, venous diseases, venous thrombosis, ventricularfibrillation, viral and fungal infections, vital encephalitis/asepticmeningitis, vital-associated hemaphagocytic syndrome, Wernicke-Korsakoffsyndrome, Wilson's disease, xenograft rejection of any organ or tissue,atrial fibrillation (sustained or paroxysmal), atrial flutter,atrioventricular block, B cell lymphoma, bone graft rejection, bonemarrow transplant (BMT) rejection, small bowel transplant rejection,spinal ataxia, bundle branch block, Burkitt's lymphoma, burns, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chromic myelocytic leukemia, chronic alcoholism, chronicinflammatory pathologies, chronic lymphocytic leukemia, chronicsalicylate intoxication, colorectal carcinoma, congestive heart failure,conjunctivitis, cor pulmonale, coronary artery disease,Creutzfeldt-Jakob disease, culture negative sepsis, cystic fibrosis,cytokine therapy associated disorders, Dementia pugilistica,demyelinating diseases, dengue hemorrhagic fever, dermatitis,dermatologic conditions, diabetic ateriosclerotic disease, Diffuses Lewybody disease, dilated congestive cardiomyopathy, disorders of the basalganglia, Down's Syndrome in middle age, drug-induced movement disordersinduced by drugs which block CNS dopamine receptors, drug sensitivity,eczema, encephalomyelitis, endocarditis, endocrinopathy, epiglottitis,Epstein Barr virus infection, erythromelalgia, extrapyramidal andcerebellar disorders, familial hematophagocytic lymphohistiocytosis,fetal thymus implant rejection, Friedreich's ataxia, functionalperipheral arterial disorders, fungal sepsis, gas gangrene, gastriculcer, glomerular nephritis, gram negative sepsis, gram positive sepsis,granulomas due to intracellular organisms, hairy cell leukemia,Hallerrorden-Spatz disease, hay fever, heart transplant rejection,hemachromatosis, hemodialysis, hemolytic uremic syndrome/thrombolyticthrombocytopenic purpura, hemorrhage, idiopathic pulmonary fibrosis,antibody mediated cytotoxicity, Asthenia, infantile spinal muscularatrophy, inflammation of the aorta, influenza A, ionizing radiationexposure, iridocyclitis/uveitis/optic neuritis, juvenile rheumatoidarthritis, juvenile spinal muscular atrophy, kidney transplantrejection, legionella, leishmaniasis, lipedema, liver transplantrejection, lymphederma, malaria, malignant Lymphoma, malignanthistiocytosis, malignant melanoma, meningococcemia,metabolic/idiopathic, migraine headache, mitochondrial multi-systemdisorder, monoclonal gammopathy, multiple myeloma, multiple systemsdegenerations (Mencel Dejerine-Thomas Shi-Drager and Machado-Joseph),myasthenia gravis, mycobacterium avium intracellulare, mycobacteriumtuberculosis, myelodyplastic syndrome, myocardial ischemic disorders,nasopharyngeal carcinoma, neonatal chronic lung disease, nephritis,nephrosis, neurodegenerative diseases, neurogenic I muscular atrophies,neutropenic fever, non-Hodgkin's lymphoma, occlusion of the abdominalaorta and its branches, occulsive arterial disorders, okt3 therapy,orchitis/epidydimitis, orchitis/vasectomy reversal procedures,organomegaly, osteoporosis, pancreas transplant rejection, pancreaticcarcinoma, paraneoplastic syndrome/hypercalcemia of malignancy,parathyroid transplant rejection, pelvic inflammatory disease, perennialrhinitis, pericardial disease, Kaposi's sarcoma, Hodgkin's disease,lymphoma, myeloma, leukaemia, malignant ascites, hematopoietic cancers,Crow-Fukase (POEMS) syndrome (polyneuropathy, organomegaly,endocrinopathy, monoclonal gammopathy, and skin changes syndrome), adiabetic condition such as insulin-dependent diabetes mellitus glaucoma,diabetic retinopathy or microangiopathy, sickle cell anaemia, chronicinflammation, synovitis, glomerulonephritis, graft rejection, Lymedisease, von Hippel Lindau disease, pemphigoid, Paget's disease,fibrosis, sarcoidosis, cirrhosis, thyroiditis, hyperviscosity syndrome,Osler-Weber-Rendu disease, chronic occlusive pulmonary disease, asthmaor edema following burns, trauma, radiation, stroke, hypoxia, ischemia,ovarian hyperstimulation syndrome, post perfusion syndrome, post pumpsyndrome, post-MI cardiotomy syndrome, preeclampsia, menometrorrhagia,endometriosis, pulmonary hypertension, infantile hemangioma, orinfection by Herpes simplex, Herpes Zoster, human immunodeficiencyvirus, parapoxvirus, protozoa or toxoplasmosis, Progressive supranucleoPalsy, primary pulmonary hypertension, radiation therapy, Raynaud'sphenomenon and disease, Refsum's disease, regular narrow QRStachycardia, renovascular hypertension, restrictive cardiomyopathy,sarcoma, senile chorea, Senile Dementia of Lewy body type, shock, skinallograft, skin changes syndrome, ocular or macular edema, ocularneovascular disease, scleritis, radial keratotomy, uveitis, vitritis,myopia, optic pits, chronic retinal detachment, post-laser treatmentcomplications, conjunctivitis, Stargardt's disease, Eales disease,retinopathy, macular degeneration, restenosis, ischemia/reperfusioninjury, ischemic stroke, vascular occlusion, carotid obstructivedisease, ulcerative colitis, inflammatory bowel disease, diabetes,diabetes mellitus, insulin dependent diabetes mellitus, allergicdiseases, dermatitis scleroderma, graft versus host disease, organtransplant rejection (including but not limited to bone marrow and solidorgan rejection), acute or chronic immune disease associated with organtransplantation, sarcoidosis, disseminated intravascular coagulation,Kawasaki's disease, nephrotic syndrome, chronic fatigue syndrome,Wegener's granulomatosis, Henoch-Schoenlein purpurea, microscopicvasculitis of the kidneys, chronic active hepatitis, septic shock, toxicshock syndrome, sepsis syndrome, cachexia, infectious diseases,parasitic diseases, acquired immunodeficiency syndrome, acute transversemyelitis, Huntington's chorea, stroke, primary biliary cirrhosis,hemolytic anemia, malignancies, Addison's disease, idiopathic Addison'sdisease, sporadic, polyglandular deficiency type I and polyglandulardeficiency type II, Schmidt's syndrome, adult (acute) respiratorydistress syndrome, alopecia, alopecia greata, seronegative arthropathy,arthropathy, Reiter's disease, psoriatic arthropathy, ulcerative coliticarthropathy, enteropathic synovitis, chlamydia, yersinia and salmonellaassociated arthropathy, atheromatous disease/arteriosclerosis, atopicallergy, autoimmune bullous disease, pemphigus vulgaris, pemphigusfoliaceus, pemphigoid, linear IgA disease, autoimmune haemolyticanaemia, Coombs positive haemolytic anaemia, acquired perniciousanaemia, juvenile pernicious anaemia, peripheral vascular disorders,peritonitis, pernicious anemia, myalgic encephalitis/Royal Free Disease,chronic mucocutaneous candidiasis, giant cell arteritis, primarysclerosing hepatitis, cryptogenic autoimmune hepatitis, AcquiredImmunodeficiency Disease Syndrome, Acquired Immunodeficiency RelatedDiseases, Hepatitis A, Hepatitis B, Hepatitis C, H is bundle arrythmias,HIV infection/HIV neuropathy, common varied immunodeficiency (commonvariable hypogammaglobulinaemia), dilated cardiomyopathy, femaleinfertility, ovarian failure, premature ovarian failure, fibrotic lungdisease, chronic wound healing, cryptogenic fibrosing alveolitis,post-inflammatory interstitial lung disease, interstitial pneumonitis,pneumocystis carinii pneumonia, pneumonia, connective tissue diseaseassociated interstitial lung disease, mixed connective tissue disease,associated lung disease, systemic sclerosis associated interstitial lungdisease, rheumatoid arthritis associated interstitial lung disease,systemic lupus erythematosus associated lung disease,dermatomyositis/polymyositis associated lung disease, Sjögren's diseaseassociated lung disease, ankylosing spondylitis associated lung disease,vasculitic diffuse lung disease, haemosiderosis associated lung disease,drug-induced interstitial lung disease, radiation fibrosis,bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocyticinfiltrative lung disease, postinfectious interstitial lung disease,gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis(classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis(anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type Binsulin resistance with acanthosis nigricans, hypoparathyroidism, acuteimmune disease associated with organ transplantation, chronic immunedisease associated with organ transplantation, osteoarthrosis, primarysclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathicleucopaenia, autoimmune neutropaenia, renal disease NOS,glomerulonephritides, microscopic vasulitis of the kidneys, Lymedisease, discoid lupus erythematosus, male infertility idiopathic orNOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympatheticophthalmia, pulmonary hypertension secondary to connective tissuedisease, acute and chronic pain (different forms of pain), Goodpasture'ssyndrome, pulmonary manifestation of polyarteritis nodosa, acuterheumatic fever, rheumatoid spondylitis, Still's disease, systemicsclerosis, Sjögren's syndrome, Takayasu's disease/arteritis, autoimmunethrombocytopaenia, toxicity, transplants, idiopathic thrombocytopaenia,autoimmune thyroid disease, hyperthyroidism, goitrous autoimmunehypothyroidism (Hashimoto's disease), atrophic autoimmunehypothyroidism, primary myxoedema, phacogenic uveitis, primaryvasculitis, vitiligo, acute liver disease, chronic liver diseases,alcoholic cirrhosis, alcohol-induced liver injury, choleosatatis,idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholicSteatohepatitis, allergy and asthma, group B streptococci infection,mental disorders (e.g., depression and schizophrenia), Th2 Type and Th1Type mediated diseases, and diseases involving inappropriatevascularization for example diabetic retinopathy, retinopathy ofprematurity, choroidal neovascularization due to age-related maculardegeneration, and infantile hemangiomas in human beings. In addition,such compounds may be useful in the treatment of disorders such asascites, effusions, and exudates, including for example macular edema,cerebral edema, acute lung injury, adult respiratory distress syndrome,proliferative disorders such as restenosis, fibrotic disorders such ashepatic cirrhosis and atherosclerosis, mesangial cell proliferativedisorders such as diabetic nephropathy, malignant nephrosclerosis,thrombotic microangiopathy syndromes, and glomerulopathies, myocardialangiogenesis, coronary and cerebral collaterals, ischemic limbangiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacterrelated diseases, virally-induced angiogenic disorders, preeclampsia,menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma andretinopathies such as those associated with diabetic retinopathy,retinopathy of prematurity, age-related macular degeneration, acuteidiopathic polyneuritis, acuter or chronic immune disease associatedwith organ transplantation, acute inflammatory demyelinatingpolyradiculoneuropathy, acute ischemia, adult Still's disease, allergy,anaphylaxis, anti-phospholipid antibody syndrome, aplastic anemia,atopic eczema, atopic dermatitis, autoimmune dermatitis, autoimmunediabetes, autoimmune disorder associated with streptococcus infection,autoimmune enteropathy, autoimmune hepatitis, autoimmune hearing loss,autoimmune lymphoproliferative syndrome, autoimmune myocarditis,autoimmune neutropenia, autoimmune premature ovarian failure, autoimmunethrombocytopenia, autoimmune uveitis, Behcet's disease, blepharitis,bronchiectasis, bullous pemphigoid, catastrophic antiphospholipidsyndrome, celiac disease, cervical spondylosis, chronic ischemia,cicatricial pemphigoid, clinical isolated syndrome with risk formultiple sclerosis, childhood onset psychiatric disorder, dacrocystitis,dermatomyositis, disc herniation, disc prolapse, drug induced immunehemolytic anemia, endophthalmitis, episcleritis, erythema multiforme,erythema multiforme major, gestational pemphigoid, Guillain-Barresyndrome, heart failure, Hughes syndrome, idiopathic Parkinson'sdisease, idiopathic interstitial pneumonia, IgE-mediated allergy, immunehemolytic anemia, inclusion body myositis, infectious ocularinflammatory disease, inflammatory demyelinating disease, inflammatoryheart disease, inflammatory kidney disease, IPF/UIP, iritis, keratitis,keratojuntivitis sicca, Kussmaul disease or Kussmaul-Meier disease,Landry's paralysis, Langerhan's cell hisiocytosis, livedo reticularis,microscopic polyangiitis, morbus bechterev, motor neuron disorders,mucous membrane pemphigoid, primary progressive multiple sclerosis,secondary progressive multiple sclerosis, relapsing remitting multiplesclerosis, multiple organ failure, myelodysplastic syndrome, nerve rootdisorder, neuropathy, Non-A Non-B hepatitis, osteolysis, ovarian cancer,pauciarticular JRA, peripheral artery occlusive disease (PAOD),peripheral vascular disease (PVD), peripheral artery disease, phlebitis,polychondritis, polymyalgia rheumatica, poliosis, polyarticular JRA,polyendocrine deficiency syndrome, polymyositis, post-pump syndrome,primary parkinsonism, prostatitis, psoratic arthropathy, pure red cellaplasia, primary adrenal insufficiency, Reiter's disease, recurrentneuromyelitis optica, rheumatic heart disease, SAPHO (synovitis, acne,pustulosis, hyperostosis, and osteitis), scleroderma, secondaryamyloidosis, shock lung, sciatica, secondary adrenal insufficiency,septic arthritis, seronegative arthopathy, silicone associatedconnective tissue disease, Sneddon-Wilkinson Dermatosis, spondilitisankylosans, Stevens-Johnson Syndrome, systemic inflammatory responsesyndrome, temporal arteritis, toxoplasmic retinitis, toxic epidermalnecrolysis, TRAPS (Tumor Necrosis factor receptor), type 1 allergicreaction, type II diabetes, urticaria, usual interstitial pneumonia,vernal conjunctivitis, viral retinitis, Vogt-Koyanagi-Harada syndrome(VKH syndrome) and wet macular degeneration.

In a nineteenth embodiment the invention provides a method according tothe nineteenth embodiment wherein the condition is selected from thegroup consisting of rheumatoid arthritis, osteoarthritis, asthma andmultiple sclerosis.

In a twentieth embodiment the invention provides a pharmaceuticalcomposition comprising a compound of Formula (I)

and a pharmaceutically acceptable carrier or excipient, wherein

-   -   R^(a) is H or optionally substituted (C₁-C₆)alkyl;    -   R^(b) is selected from the optionally substituted group        consisting of —(CH₂)_(n)-aryl, —CH(CH₃)-aryl,        —(CH₂)_(n)-aryl-aryl, —(CH₂)_(n)-aryl-heteroaryl,        —(CH₂)_(n)—(C₃-C₈)cycloalkyl, —(CH₂)_(n)-heteroaryl,        —(CH₂)_(n)-heterocyclyl and —(C₃-C₈)cycloalkyl-aryl; or    -   R^(a) and R^(b) are taken together with the nitrogen to form        2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl, optionally        substituted piperidinyl or optionally substituted pyrrolidinyl;    -   Y is selected from the optionally substituted group consisting        of 5,6,7,8-tetrahydro[1,6]naphthridinyl,        —NH—(CH₂)_(n)-heterocycyl wherein the NH is attached to the        carbonyl and -heterocyclyl-aryl wherein the heterocyclyl is        attached to the carbonyl; and    -   n is 0, 1 or 2.

DETAILED DESCRIPTION OF THE INVENTION

In a related aspect the invention provides a method for antagonizingCCR2 in a human subject suffering from a disorder in which CCR2 activityis detrimental, comprising administering to the human subject a compoundof Formula (I)

such that CCR2 activity in the human subject is inhibited and treatmentis achieved.

Many autoimmune diseases and disease associated with chronicinflammation, as well as acute responses, have been linked to activationof CCR2. The present compounds are useful in the treatment ofinflammatory disorders including, but not limited to rheumatoidarthritis, osteoarthritis, asthma, chronic obstructive pulmonary disease(COPD), sepsis, psoriasis, psoriatic arthritis, inflammatory boweldisease, Crohn's disease, lupus, multiple sclerosis, juvenile chronicarthritis, Lyme arthritis, reactive arthritis, septic arthritis,spondyloarthropathy and systemic lupus erythematosus.

The compounds of the invention are also useful in the treatment ofcardiovascular disorders, such as acute myocardial infarction, acutecoronary syndrome, chronic heart failure, atherosclerosis, viralmyocarditis, cardiac allograft rejection, and sepsis-associated cardiacdysfunction. Furthermore, the compounds of the present invention arealso useful for the treatment of central nervous system disorders suchas meningococcal meningitis, Alzheimer's disease and Parkinson'sdisease.

A compound of Formula (I) or a pharmaceutically acceptable salt thereofor pharmaceutical compositions containing a therapeutically effectiveamount thereof is useful in the treatment of a disorder selected fromthe group comprising CNS system disorders, arthritis, rheumatoidarthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis,psoriatic arthritis, reactive arthritis, and septic arthritis,spondyloarthropathy, systemic lupus erythematosus, Crohn's disease,ulcerative colitis, inflammatory bowel disease, insulin dependentdiabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis,dermatitis scleroderma, graft versus host disease, organ transplantrejection (including but not limited to bone marrow and solid organrejection), acute or chronic immune disease associated with organtransplantation, sarcoidosis, atherosclerosis, disseminatedintravascular coagulation, Kawasaki's disease, Grave's disease,nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis,Henoch-Schoenlein purpurea, microscopic vasculitis of the kidneys,chronic active hepatitis, uveitis, septic shock, toxic shock syndrome,sepsis syndrome, cachexia, infectious diseases, parasitic diseases,acquired immunodeficiency syndrome, acute transverse myelitis,Huntington's chorea, Parkinson's disease, Alzheimer's disease, stroke,primary biliary cirrhosis, hemolytic anemia, malignancies, heartfailure, myocardial infarction, Addison's disease, sporadic,polyglandular deficiency type I and polyglandular deficiency type II,Schmidt's syndrome, adult (acute) respiratory distress syndrome,alopecia, alopecia greata, seronegative arthopathy, arthropathy,Reiter's disease, psoriatic arthropathy, ulcerative colitic arthropathy,enteropathic synovitis, chlamydia, Yersinia and salmonella associatedarthropathy, atheromatous disease/arteriosclerosis, atopic allergy,autoimmune bullous disease, pemphigus vulgaris, pemphigus foliaceus,pemphigoid, linear IgA disease, autoimmune haemolytic anaemia, Coombspositive haemolytic anaemia, acquired pernicious anaemia, juvenilepernicious anaemia, myalgic encephalitis/Royal Free Disease, chronicmucocutaneous candidiasis, giant cell arteritis, primary sclerosinghepatitis, cryptogenic autoimmune hepatitis, Acquired ImmunodeficiencyDisease Syndrome, Acquired Immunodeficiency Related Diseases, HepatitisB, Hepatitis C, common varied immunodeficiency (common variablehypogammaglobulinaemia), dilated cardiomyopathy, female infertility,ovarian failure, premature ovarian failure, fibrotic lung disease,chronic wound healing, cryptogenic fibrosing alveolitis,post-inflammatory interstitial lung disease, interstitial pneumonitis,connective tissue disease associated interstitial lung disease, mixedconnective tissue disease associated lung disease, systemic sclerosisassociated interstitial lung disease, rheumatoid arthritis associatedinterstitial lung disease, systemic lupus erythematosus associated lungdisease, dermatomyositis/polymyositis associated lung disease, Sjögren'sdisease associated lung disease, ankylosing spondylitis associated lungdisease, vasculitic diffuse lung disease, haemosiderosis associated lungdisease, drug-induced interstitial lung disease, radiation fibrosis,bronchiolitis obliterans, chronic eosinophilic pneumonia, lymphocyticinfiltrative lung disease, postinfectious interstitial lung disease,gouty arthritis, autoimmune hepatitis, type-1 autoimmune hepatitis(classical autoimmune or lupoid hepatitis), type-2 autoimmune hepatitis(anti-LKM antibody hepatitis), autoimmune mediated hypoglycaemia, type Binsulin resistance with acanthosis nigricans, hypoparathyroidism, acuteimmune disease associated with organ transplantation, chronic immunedisease associated with organ transplantation, osteoarthrosis, primarysclerosing cholangitis, psoriasis type 1, psoriasis type 2, idiopathicleucopaenia, autoimmune neutropaenia, renal disease NOS,glomerulonephritides, microscopic vasulitis of the kidneys, Lymedisease, discoid lupus erythematosus, male infertility idiopathic orNOS, sperm autoimmunity, multiple sclerosis (all subtypes), sympatheticophthalmia, pulmonary hypertension secondary to connective tissuedisease, Goodpasture's syndrome, pulmonary manifestation ofpolyarteritis nodosa, acute rheumatic fever, rheumatoid spondylitis,Still's disease, systemic sclerosis, Sjögren's syndrome, Takayasu'sdisease/arteritis, autoimmune thrombocytopaenia, idiopathicthrombocytopaenia, autoimmune thyroid disease, hyperthyroidism, goitrousautoimmune hypothyroidism (Hashimoto's disease), atrophic autoimmunehypothyroidism, primary myxoedema, phacogenic uveitis, primaryvasculitis, vitiligo, acute liver disease, chronic liver diseases,alcoholic cirrhosis, alcohol-induced liver injury, choleosatatis,idiosyncratic liver disease, Drug-Induced hepatitis, Non-alcoholicSteatohepatitis, allergy and asthma, group B streptococci (GBS)infection, mental disorders (e.g., depression and schizophrenia), Th2Type and Th1 Type mediated diseases, acute and chronic pain (differentforms of pain), and cancers such as lung, breast, stomach, bladder,colon, pancreas, ovarian, prostate and rectal cancer and hematopoieticmalignancies (leukemia and lymphoma), and hematopoietic malignancies(leukemia and lymphoma), Abetalipoprotemia, Acrocyanosis, acute andchronic parasitic or infectious processes, acute leukemia, acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), acute orchronic bacterial infection, acute pancreatitis, acute renal failure,adenocarcinomas, aerial ectopic beats, AIDS dementia complex,alcohol-induced hepatitis, allergic conjunctivitis, allergic contactdermatitis, allergic rhinitis, allograft rejection, alpha-1-antitrypsindeficiency, amyotrophic lateral sclerosis, anemia, angina pectoris,anterior horn cell degeneration, anti cd3 therapy, antiphospholipidsyndrome, anti-receptor hypersensitivity reactions, aordic andperipheral aneuryisms, aortic dissection, arterial hypertension,arteriosclerosis, arteriovenous fistula, ataxia, atrial fibrillation(sustained or paroxysmal), atrial flutter, atrioventricular block, Bcell lymphoma, bone graft rejection, bone marrow transplant (BMT)rejection, bundle branch block, Burkitt's lymphoma, Burns, cardiacarrhythmias, cardiac stun syndrome, cardiac tumors, cardiomyopathy,cardiopulmonary bypass inflammation response, cartilage transplantrejection, cerebellar cortical degenerations, cerebellar disorders,chaotic or multifocal atrial tachycardia, chemotherapy associateddisorders, chromic myelocytic leukemia (CML), chronic alcoholism,chronic inflammatory pathologies, chronic lymphocytic leukemia (CLL),chronic obstructive pulmonary disease (COPD), chronic salicylateintoxication, colorectal carcinoma, congestive heart failure,conjunctivitis, contact dermatitis, cor pulmonale, coronary arterydisease, Creutzfeldt-Jakob disease, culture negative sepsis, cysticfibrosis, cytokine therapy associated disorders, Dementia pugilistica,demyelinating diseases, dengue hemorrhagic fever, dermatitis,dermatologic conditions, diabetes, diabetes mellitus, diabeticateriosclerotic disease, Diffuse Lewy body disease, dilated congestivecardiomyopathy, disorders of the basal ganglia, Down's Syndrome inmiddle age, drug-induced movement disorders induced by drugs which blockCNS dopamine receptors, drug sensitivity, eczema, encephalomyelitis,endocarditis, endocrinopathy, epiglottitis, epstein-barr virusinfection, erythromelalgia, extrapyramidal and cerebellar disorders,familial hematophagocytic lymphohistiocytosis, fetal thymus implantrejection, Friedreich's ataxia, functional peripheral arterialdisorders, fungal sepsis, gas gangrene, gastric ulcer, glomerularnephritis, graft rejection of any organ or tissue, gram negative sepsis,gram positive sepsis, granulomas due to intracellular organisms, hairycell leukemia, Hallerrorden-Spatz disease, hashimoto's thyroiditis, hayfever, heart transplant rejection, hemachromatosis, hemodialysis,hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura,hemorrhage, hepatitis (A), His bundle arrythmias, HIV infection/HIVneuropathy, Hodgkin's disease, hyperkinetic movement disorders,hypersensitivity reactions, hypersensitivity pneumonitis, hypertension,hypokinetic movement disorders, hypothalamic-pituitary-adrenal axisevaluation, idiopathic Addison's disease, idiopathic pulmonary fibrosis,antibody mediated cytotoxicity, Asthenia, infantile spinal muscularatrophy, inflammation of the aorta, influenza a, ionizing radiationexposure, iridocyclitis/uveitis/optic neuritis, ischemia-reperfusioninjury, ischemic stroke, juvenile rheumatoid arthritis, juvenile spinalmuscular atrophy, Kaposi's sarcoma, kidney transplant rejection,legionella, leishmaniasis, leprosy, lesions of the corticospinal system,lipedema, liver transplant rejection, lymphederma, malaria, malignantLymphoma, malignant histiocytosis, malignant melanoma, meningitis,meningococcemia, metabolic/idiopathic, migraine headache, mitochondrialmultisystem disorder, mixed connective tissue disease, monoclonalgammopathy, multiple myeloma, multiple systems degenerations (MencelDejerine-Thomas Shi-Drager and Machado-Joseph), myasthenia gravis,mycobacterium avium intracellulare, mycobacterium tuberculosis,myelodyplastic syndrome, myocardial infarction, myocardial ischemicdisorders, nasopharyngeal carcinoma, neonatal chronic lung disease,nephritis, nephrosis, neurodegenerative diseases, neurogenic I muscularatrophies, neutropenic fever, non-Hodgkin's lymphoma, occlusion of theabdominal aorta and its branches, occulsive arterial disorders, okt3therapy, orchitis/epidydimitis, orchitis/vasectomy reversal procedures,organomegaly, osteoporosis, pancreas transplant rejection, pancreaticcarcinoma, paraneoplastic syndrome/hypercalcemia of malignancy,parathyroid transplant rejection, pelvic inflammatory disease, perennialrhinitis, pericardial disease, peripheral atherlosclerotic disease,peripheral vascular disorders, peritonitis, pernicious anemia,pneumocystis carinii pneumonia, pneumonia, POEMS syndrome(polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy,and skin changes syndrome), post perfusion syndrome, post pump syndrome,post-MI cardiotomy syndrome, preeclampsia, Progressive supranucleoPalsy, primary pulmonary hypertension, radiation therapy, Raynaud'sphenomenon and disease, Raynoud's disease, Refsum's disease, regularnarrow QRS tachycardia, renovascular hypertension, reperfusion injury,restrictive cardiomyopathy, sarcomas, scleroderma, senile chorea, SenileDementia of Lewy body type, seronegative arthropathies, shock, sicklecell anemia, skin allograft rejection, skin changes syndrome, smallbowel transplant rejection, solid tumors, specific arrythmias, spinalataxia, spinocerebellar degenerations, streptococcal myositis,structural lesions of the cerebellum, Subacute sclerosingpanencephalitis, Syncope, syphilis of the cardiovascular system,systemic anaphalaxis, systemic inflammatory response syndrome, systemiconset juvenile rheumatoid arthritis, T-cell or FAB ALL, Telangiectasia,thromboangitis obliterans, thrombocytopenia, toxicity, transplants,trauma/hemorrhage, type III hypersensitivity reactions, type IVhypersensitivity, unstable angina, uremia, urosepsis, urticaria,valvular heart diseases, varicose veins, vasculitis, venous diseases,venous thrombosis, ventricular fibrillation, viral and fungalinfections, vital encephalitis/aseptic meningitis, vital-associatedhemaphagocytic syndrome, Wernicke-Korsakoff syndrome, Wilson's disease,xenograft rejection of any organ or tissue, and diseases involvinginappropriate vascularization for example diabetic retinopathy,retinopathy of prematurity, choroidal neovascularization due toage-related macular degeneration, and infantile hemangiomas in humanbeings. In addition, such compounds may be useful in the treatment ofdisorders such as edema, ascites, effusions, and exudates, including forexample macular edema, cerebral edema, acute lung injury, adultrespiratory distress syndrome (ARDS), proliferative disorders such asrestenosis, fibrotic disorders such as hepatic cirrhosis andatherosclerosis, mesangial cell proliferative disorders such asglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombotic microangiopathy syndromes, and glomerulopathies, myocardialangiogenesis, coronary and cerebral collaterals, ischemic limbangiogenesis, ischemia/reperfusion injury, peptic ulcer Helicobacterrelated diseases, virally-induced angiogenic disorders, Crow-Fukasesyndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever,rubeosis, neovascular glaucoma and retinopathies such as thoseassociated with diabetic retinopathy, retinopathy of prematurity,age-related macular degeneration or a central nervous system disorder.In addition, these compounds can be used as active agents against solidtumors, malignant ascites, von Hippel Lindau disease, hematopoieticcancers and hyperproliferative disorders such as thyroid hyperplasia(especially Grave's disease), and cysts (such as hypervascularity ofovarian stroma characteristic of polycystic ovarian syndrome(Stein-Leventhal syndrome) and polycystic kidney disease since suchdiseases require a proliferation of blood vessel cells for growth and/ormetastasis.

Compounds of Formula (I) of the invention can be used alone or incombination with another therapeutic agent to treat such diseases, saidadditional agent being selected by the skilled artisan for its intendedpurpose. For example, the additional agent can be a therapeutic agentart-recognized as being useful to treat the disease or condition beingtreated by the compound of the present invention. The additional agentalso can be an agent that imparts a beneficial attribute to thetherapeutic composition e.g., an agent that affects the viscosity of thecomposition.

It should further be understood that the combinations which are to beincluded within this invention are those combinations useful for theirintended purpose. The agents set forth below are illustrative forpurposes and not intended to be limited. The combinations, which arepart of this invention, can be the compounds of the present inventionand at least one additional agent selected from the lists below. Thecombination can also include more than one additional agent, e.g., twoor three additional agents if the combination is such that the formedcomposition can perform its intended function.

For example, in the treatment or prevention of inflammation, the presentcompounds may be used in conjunction or combination with ananti-inflammatory or analgesic agent such as an opiate agonist, alipoxygenase inhibitor, such as an inhibitor of 5-lipoxygenase, acyclooxygenase inhibitor, such as a cyclooxygenase-2 inhibitor, aninterleukin inhibitor, such as an interleukin-1 inhibitor, an NMDAantagonist, an inhibitor of nitric oxide or an inhibitor of thesynthesis of nitric oxide, a non-steroidal anti-inflammatory agent, or acytokine-suppressing anti-inflammatory agent, for example with acompound such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen,indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, asteroidal analgesic, sufentanyl, sunlindac, tenidap, and the like.Similarly, the instant compounds may be administered with a painreliever; a potentiator such as caffeine, an H2-antagonist, simethicone,aluminum or magnesium hydroxide; a decongestant such as phenylephrine,phenylpropanolamine, pseudophedrine, oxymetazoline, ephinephrine,naphazoline, xylometazoline, propylhexedrine, or levo-desoxy-ephedrine;an antiitussive such as codeine, hydrocodone, caramiphen,carbetapentane, or dextromethorphan; a diuretic; and a sedating ornon-sedating antihistamine Likewise, compounds of the present inventionmay be used in combination with other drugs that are used in thetreatment/prevention/suppression or amelioration of the diseases orconditions for which compounds of the present invention are useful. Suchother drugs may be administered, by a route and in an amount commonlyused therefor, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention. Examples of other active ingredients that may becombined with a compound of the present invention, either administeredseparately or in the same pharmaceutical compositions, include, but arenot limited to: (a) VLA-4 antagonists, (b) steroids such asbeclomethasone, methylprednisolone, betamethasone, prednisone,dexamethasone, and hydrocortisone; (c) immunosuppressants such ascyclosporine (cyclosporine A, Sandimmune®, Neoral®), tacrolimus (FK-506,Prograf®), rapamycin (sirolimus, Rapamune®) and other FK-506 typeimmunosuppressants, and mycophenolate, e.g., mycophenolate mofetil(CellCept®); (d) antihistamines (H1-histamine antagonists) such asbromopheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine,clemastine, diphenhydramine, diphenylpyraline, tripelennamine,hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine,cyproheptadine, antazoline, pheniramine pyrilamine, astemizole,terfenadine, loratadine, cetirizine, fexofenadine,descarboethoxyloratadine, and the like; (e) non-steroidalanti-asthmatics such as beta.2-agonists (terbutaline, metaproterenol,fenoterol, isoetharine, albuterol, bitolterol, and pirbuterol),theophylline, cromolyn sodium, atropine, ipratropium bromide,leukotriene antagonists (zafirlukast, montelukast, pranlukast,iralukast, pobilukast, SKB-106,203), leukotriene biosynthesis inhibitors(zileuton, BAY-1005); (f) non-steroidal antiinflammatory agents (NSAIDs)such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxicacid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen,ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin,pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen),acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac,diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac,isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, andzomepirac), fenamic acid derivatives (flufenamic acid, meclofenamicacid, mefenamic acid, niflumic acid and tolfenamic acid),biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams(isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazone,bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone);(g) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Celebrex®)and rofecoxib (Vioxx®); (h) inhibitors of phosphodiesterase type IV(PDE-IV); (i) gold compounds such as auranofin and aurothioglucose, (j)inhibitors of phosphodiesterase type IV (PDE-IV); (k) other antagonistsof the chemokine receptors, especially CCR1, CCR2, CCR3, CCR5, CCR6,CCR8 and CCR10; (l) cholesterol lowering agents such as HMG-CoAreductase inhibitors (lovastatin, simvastatin and pravastatin,fluvastatin, atorvastatin, and other statins), sequestrants(cholestyramine and colestipol), nicotinic acid, fenofibric acidderivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate), andprobucol; (m) anti-diabetic agents such as insulin, sulfonylureas,biguanides (metformin), α-glucosidase inhibitors (acarbose) andglitazones (troglitazone and pioglitazone); (n) preparations ofinterferon beta (interferon β-1α; interferon β-1b); (o) etanercept(Enbrel®), (p) antibody therapies such as orthoclone (OKT3), daclizumab(Zenapax®), infliximab (Remicade®), basiliximab (Simulect®) andanti-CD40 ligand antibodies (e.g., MRP-1); and (q) other compounds suchas 5-aminosalicylic acid and pro-drugs thereof, hydroxychloroquine,D-penicillamine, antimetabolites such as azathioprene and6-mercaptopurine, and cytotoxic cancer chemotherapeutic agents. Theweight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith an NSAID the weight ratio of the compound of the present inventionto the NSAID will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of thepresent invention and other active ingredients will generally also bewithin the aforementioned range, but in each case, an effective dose ofeach active ingredient should be used.

Immunosuppressants within the scope of the present invention furtherinclude, but are not limited to, leflunomide, RAD001, ERL080, FTY720,CTLA-4, antibody therapies such as orthoclone (OKT3), daclizumab(Zenapax®) and basiliximab (Simulect®), and antithymocyte globulins suchas thymoglobulins.

In particularly preferred embodiments, the present methods are directedto the treatment or prevention of multiple sclerosis using a compound ofthe invention either alone or in combination with a second therapeuticagent selected from betaseron, avonex, azathioprene (Imurek®, Imuran®),capoxone, prednisolone and cyclophosphamide. When used in combination,the practitioner can administer a combination of the therapeutic agents,or administration can be sequential.

In still other particularly preferred embodiments, the present methodsare directed to the treatment or prevention of rheumatoid arthritis,wherein the compound of the invention is administered either alone or incombination with a second therapeutic agent selected from the groupconsisting of methotrexate, sulfasalazine, hydroxychloroquine,cyclosporine A, D-penicillamine, infliximab (Remicade®), etanercept(Enbrel®), adalimumab (Humira®), auranofin and aurothioglucose.

In yet other particularly preferred embodiments, the present methods aredirected to the treatment or prevention of an organ transplant conditionwherein the compound of the invention is used alone or in combinationwith a second therapeutic agent selected from the group consisting ofcyclosporine A, FK-506, rapamycin, mycophenolate, prednisolone,azathioprene, cyclophosphamide and an antilymphocyte globulin.

Preferred combinations are non-steroidal anti-inflammatory drug(s) alsoreferred to as NSAIDS which include drugs like ibuprofen. Otherpreferred combinations are corticosteroids including prednisolone; thewell known side-effects of steroid use can be reduced or even eliminatedby tapering the steroid dose required when treating patients incombination with the CCR2 antagonists of this invention. Non-limitingexamples of therapeutic agents for rheumatoid arthritis with which acompound of Formula (I) of the invention can be combined include thefollowing: cytokine suppressive anti-inflammatory drug(s) (CSAIDs);antibodies to or antagonists of other human cytokines or growth factors,for example, TNF, LT, IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8,IL-12, IL-15, IL-16, IL-21, IL-23, interferons, EMAP-II, GM-CSF, FGF,and PDGF. S/T kinase inhibitors of the invention can be combined withantibodies to cell surface molecules such as CD2, CD3, CD4, CD8, CD25,CD28, CD30, CD40, CD45, CD69, CD80 (B7.1), CD86 (B7.2), CD90, CTLA ortheir ligands including CD154 (gp39 or CD40L).

Preferred combinations of therapeutic agents may interfere at differentpoints in the autoimmune and subsequent inflammatory cascade; preferredexamples include TNF antagonists like chimeric, humanized or human TNFantibodies, D2E7 (HUMIRA®), (U.S. Pat. No. 6,090,382), CA2 (REMICADE™),CDP 571, and soluble p55 or p75 TNF receptors, derivatives, thereof,(p75TNFRIgG (ENBREL™) or p55TNFRIgG (Lenercept), and also TNFαconverting enzyme (TACE) inhibitors; similarly IL-1 inhibitors(Interleukin-1-converting enzyme inhibitors, IL-1RA etc.) may beeffective for the same reason. Other preferred combinations includeInterleukin 11. Yet other preferred combinations are the other keyplayers of the autoimmune response which may act parallel to, dependenton or in concert with IL-18 function; especially preferred are IL-12antagonists including IL-12 antibodies or soluble IL-12 receptors, orIL-12 binding proteins. It has been shown that IL-12 and IL-18 haveoverlapping but distinct functions and a combination of antagonists toboth may be most effective. Yet another preferred combination arenon-depleting anti-CD4 inhibitors. Yet other preferred combinationsinclude antagonists of the co-stimulatory pathway CD80 (B7.1) or CD86(B7.2) including antibodies, soluble receptors or antagonistic ligands.

A compound of Formula (I) of the invention may also be combined withagents, such as methotrexate, 6-MP, azathioprine sulphasalazine,mesalazine, olsalazine chloroquinine/hydroxychloroquine, pencillamine,aurothiomalate (intramuscular and oral), azathioprine, cochicine,corticosteroids (oral, inhaled and local injection), beta-2adrenoreceptor agonists (salbutamol, terbutaline, salmeteral), xanthines(theophylline, aminophylline), cromoglycate, nedocromil, ketotifen,ipratropium and oxitropium, cyclosporin, FK506, rapamycin, mycophenolatemofetil, leflunomide, NSAIDs, for example, ibuprofen, corticosteroidssuch as prednisolone, phosphodiesterase inhibitors, adensosine agonists,antithrombotic agents, complement inhibitors, adrenergic agents, agentswhich interfere with signalling by proinflammatory cytokines such asTNFα or IL-1 (e.g. IRAK, NIK, IKK, p38 or MAP kinase inhibitors), IL-1βconverting enzyme inhibitors, T-cell signalling inhibitors such askinase inhibitors, metalloproteinase inhibitors, sulfasalazine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors and the derivatives p75TNFRIgG (Enbrel™ and p55TNFRIgG(Lenercept)), sIL-1RI, sIL-1RII, sIL-6R), antiinflammatory cytokines(e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ), celecoxib, folic acid,hydroxychloroquine sulfate, rofecoxib, etanercept, infliximab, naproxen,valdecoxib, sulfasalazine, methylprednisolone, meloxicam,methylprednisolone acetate, gold sodium thiomalate, aspirin,triamcinolone acetonide, propoxyphene napsylate/apap, folate,nabumetone, diclofenac, piroxicam, etodolac, diclofenac sodium,oxaprozin, oxycodone HCl, hydrocodone bitartrate/apap, diclofenacsodium/misoprostol, fentanyl, anakinra, tramadol HCl, salsalate,sulindac, cyanocobalamin/fa/pyridoxine, acetaminophen, alendronatesodium, prednisolone, morphine sulfate, lidocaine hydrochloride,indomethacin, glucosamine sulf/chondroitin, amitriptyline HCl,sulfadiazine, oxycodone HCl/acetaminophen, olopatadine HCl misoprostol,naproxen sodium, omeprazole, cyclophosphamide, rituximab, IL-1 TRAP,MRA, CTLA4-IG, IL-18 BP, anti-IL-12, Anti-IL15, BIRB-796, SC10-469,VX-702, AMG-548, VX-740, Roflumilast, IC-485, CDC-801, and Mesopram.Preferred combinations include methotrexate or leflunomide and inmoderate or severe rheumatoid arthritis cases, cyclosporine and anti-TNFantibodies as noted above.

Non-limiting examples of therapeutic agents for inflammatory boweldisease with which a compound of Formula (I) of the invention can becombined include the following: budenoside; epidermal growth factor;corticosteroids; cyclosporin, sulfasalazine; aminosalicylates;6-mercaptopurine; azathioprine; metronidazole; lipoxygenase inhibitors;mesalamine; olsalazine; balsalazide; antioxidants; thromboxaneinhibitors; IL-1 receptor antagonists; anti-IL-1β monoclonal antibodies;anti-IL-6 monoclonal antibodies; growth factors; elastase inhibitors;pyridinyl-imidazole compounds; antibodies to or antagonists of otherhuman cytokines or growth factors, for example, TNF, LT, IL-1, IL-2,IL-6, IL-7, IL-8, IL-12, IL-15, IL-16, EMAP-II, GM-CSF, FGF, and PDGF;cell surface molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30,CD40, CD45, CD69, CD90 or their ligands; methotrexate; cyclosporine;FK506; rapamycin; mycophenolate mofetil; leflunomide; NSAIDs, forexample, ibuprofen; corticosteroids such as prednisolone;phosphodiesterase inhibitors; adenosine agonists; antithrombotic agents;complement inhibitors; adrenergic agents; agents which interfere withsignalling by proinflammatory cytokines such as TNFα or IL-1 (e.g. IRAK,NIK, IKK, or MAP kinase inhibitors); IL-1β converting enzyme inhibitors;TNFα converting enzyme inhibitors; T-cell signalling inhibitors such askinase inhibitors; metalloproteinase inhibitors; sulfasalazine;azathioprine; 6-mercaptopurines; angiotensin converting enzymeinhibitors; soluble cytokine receptors and derivatives thereof (e.g.soluble p55 or p75 TNF receptors, sIL-1RI, sIL-1RII, sIL-6R) andantiinflammatory cytokines (e.g. IL-4, IL-10, IL-11, IL-13 and TGFβ).Preferred examples of therapeutic agents for Crohn's disease with whicha compound of Formula (I) can be combined include the following: TNFantagonists, for example, anti-TNF antibodies, D2E7 (U.S. Pat. No.6,090,382; HUMIRA®), CA2 (REMICADE™), CDP 571, TNFR-Ig constructs,(p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™)) inhibitors and PDE4inhibitors. A compound of Formula (I) can be combined withcorticosteroids, for example, budenoside and dexamethasone;sulfasalazine, 5-aminosalicylic acid; olsalazine; and agents whichinterfere with synthesis or action of proinflammatory cytokines such asIL-1, for example, IL-1β converting enzyme inhibitors and IL-1ra; T cellsignaling inhibitors, for example, tyrosine kinase inhibitors6-mercaptopurines; IL-11; mesalamine; prednisone; azathioprine;mercaptopurine; infliximab; methylprednisolone sodium succinate;diphenoxylate/atrop sulfate; loperamide hydrochloride; methotrexate;omeprazole; folate; ciprofloxacin/dextrose-water; hydrocodonebitartrate/apap; tetracycline hydrochloride; fluocinonide;metronidazole; thimerosal/boric acid; cholestyramine/sucrose;ciprofloxacin hydrochloride; hyoscyamine sulfate; meperidinehydrochloride; midazolam hydrochloride; oxycodone HCl/acetaminophen;promethazine hydrochloride; sodium phosphate;sulfamethoxazole/trimethoprim; celecoxib; polycarbophil; propoxyphenenapsylate; hydrocortisone; multivitamins; balsalazide disodium; codeinephosphate/apap; colesevelam HCl; cyanocobalamin; folic acid;levofloxacin; methylprednisolone; natalizumab and interferon-gamma.

Non-limiting examples of therapeutic agents for multiple sclerosis withwhich a compound of Formula (I) can be combined include the following:corticosteroids; prednisolone; methylprednisolone; azathioprine;cyclophosphamide; cyclosporine; methotrexate; 4-aminopyridine;tizanidine; interferon-β1a (AVONEX®; Biogen Idec); anti-α4 antibody(Tysabri®; Biogen Idec); interferon-β1b (BETASERON®; Chiron/Berlex);interferon α-n3) (Interferon Sciences/Fujimoto), interferon-α (AlfaWassermann/J&J), interferon β1A-IF (Serono/Inhale Therapeutics),Peginterferon α 2b (Enzon/Schering-Plough), Copolymer 1 (Cop-1;COPAXONE®; Teva Pharmaceutical Industries, Inc.); hyperbaric oxygen;intravenous immunoglobulin; clabribine; antibodies to or antagonists ofother human cytokines or growth factors and their receptors, forexample, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-12, IL-23, IL-15,IL-16, EMAP-II, GM-CSF, FGF, and PDGF. A compound of Formula (I) can becombined with antibodies to cell surface molecules such as CD2, CD3,CD4, CD8, CD19, CD20, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86,CD90 or their ligands. A compound of Formula (I) may also be combinedwith agents such as methotrexate, cyclosporine, FK506, rapamycin,mycophenolate mofetil, leflunomide, NSAIDs, for example, ibuprofen,corticosteroids such as prednisolone, phosphodiesterase inhibitors,adensosine agonists, antithrombotic agents, complement inhibitors,adrenergic agents, agents which interfere with signalling byproinflammatory cytokines such as TNFα or IL-1 (e.g. IRAK, NIK, IKK, p38or MAP kinase inhibitors), IL-1β converting enzyme inhibitors, TACEinhibitors, T-cell signaling inhibitors such as kinase inhibitors,metalloproteinase inhibitors, sulfasalazine, azathioprine,6-mercaptopurines, angiotensin converting enzyme inhibitors, solublecytokine receptors and derivatives thereof (e.g. soluble p55 or p75 TNFreceptors, sIL-1RI, sIL-1RII, sIL-6R) and antiinflammatory cytokines(e.g. IL-4, IL-10, IL-13 and TGFβ).

Preferred examples of therapeutic agents for multiple sclerosis in whicha compound of Formula (I) can be combined to include interferon-β, forexample, IFNβ1a and IFNβ1b; copaxone, corticosteroids, caspaseinhibitors, for example inhibitors of caspase-1, IL-1 inhibitors, TNFinhibitors, and antibodies to CD40 ligand and CD80.

A compound of Formula (I) may also be combined with agents, such asalemtuzumab, dronabinol, daclizumab, mitoxantrone, xaliprodenhydrochloride, fampridine, glatiramer acetate, natalizumab, sinnabidol,a-immunokine NNSO3, ABR-215062, AnergiX.MS, chemokine receptorantagonists, BBR-2778, calagualine, CPI-1189, LEM (liposome encapsulatedmitoxantrone), THC.CBD (cannabinoid agonist), MBP-8298, mesopram (PDE4inhibitor), MNA-715, anti-IL-6 receptor antibody, neurovax, pirfenidoneallotrap 1258 (RDP-1258), sTNF-R1, talampanel, teriflunomide, TGF-beta2,tiplimotide, VLA-4 antagonists (for example, TR-14035, VLA4 Ultrahaler,Antegran-ELAN/Biogen), interferon gamma antagonists and IL-4 agonists.

Non-limiting examples of therapeutic agents for angina with which acompound of Formula (I) of the invention can be combined include thefollowing: aspirin, nitroglycerin, isosorbide mononitrate, metoprololsuccinate, atenolol, metoprolol tartrate, amlodipine besylate, diltiazemhydrochloride, isosorbide dinitrate, clopidogrel bisulfate, nifedipine,atorvastatin calcium, potassium chloride, furosemide, simvastatin,verapamil HCl, digoxin, propranolol hydrochloride, carvedilol,lisinopril, spironolactone, hydrochlorothiazide, enalapril maleate,nadolol, ramipril, enoxaparin sodium, heparin sodium, valsartan, sotalolhydrochloride, fenofibrate, ezetimibe, bumetanide, losartan potassium,lisinopril/hydrochlorothiazide, felodipine, captopril and bisoprololfumarate.

Non-limiting examples of therapeutic agents for ankylosing spondylitiswith which a compound of Formula (I) can be combined include thefollowing: D2E7 (U.S. Pat. No. 6,090,382; HUMIRA®), ibuprofen,diclofenac, misoprostol, naproxen, meloxicam, indomethacin, diclofenac,celecoxib, rofecoxib, sulfasalazine, methotrexate, azathioprine,minocyclin, prednisone, etanercept, and infliximab.

Non-limiting examples of therapeutic agents for asthma with which acompound of Formula (I) can be combined include the following:albuterol, salmeterol/fluticasone, montelukast sodium, fluticasonepropionate, budesonide, prednisone, salmeterol xinafoate, levalbuterolHCl, albuterol sulfate/ipratropium, prednisolone sodium phosphate,triamcinolone acetonide, beclomethasone dipropionate, ipratropiumbromide, azithromycin, pirbuterol acetate, prednisolone, theophyllineanhydrous, methylprednisolone sodium succinate, clarithromycin,zafirlukast, formoterol fumarate, influenza virus vaccine, amoxicillintrihydrate, flunisolide, allergy injection, cromolyn sodium,fexofenadine hydrochloride, flunisolide/menthol,amoxicillin/clavulanate, levofloxacin, inhaler assist device,guaifenesin, dexamethasone sodium phosphate, moxifloxacin HCl,doxycycline hyclate, guaifenesin/d-methorphan,p-ephedrine/cod/chlorphenir, gatifloxacin, cetirizine hydrochloride,mometasone furoate, salmeterol xinafoate, benzonatate, cephalexin,pe/hydrocodone/chlorphenir, cetirizine HCl/pseudoephed,phenylephrine/cod/promethazine, co deine/promethazine, cefprozil,dexamethasone, guaifenesin/pseudoephedrine,chlorpheniramine/hydrocodone, nedocromil sodium, terbutaline sulfate,epinephrine, methylprednisolone and metaproterenol sulfate.

Non-limiting examples of therapeutic agents for COPD with which acompound of Formula (I) can be combined include the following: Letairs™(ambrisentan), albuterol sulfate/ipratropium, ipratropium bromide,salmeterol/fluticasone, albuterol, salmeterol xinafoate, fluticasonepropionate, prednisone, theophylline anhydrous, methylprednisolonesodium succinate, montelukast sodium, budesonide, formoterol fumarate,triamcinolone acetonide, levofloxacin, guaifenesin, azithromycin,beclomethasone dipropionate, levalbuterol HCl, flunisolide, ceftriaxonesodium, amoxicillin trihydrate, gatifloxacin, zafirlukast,amoxicillin/clavulanate, flunisolide/menthol,chlorpheniramine/hydrocodone, metaproterenol sulfate,methylprednisolone, mometasone furoate, p-ephedrine/cod/chlorphenir,pirbuterol acetate, p-ephedrine/loratadine, terbutaline sulfate,tiotropium bromide, (R,R)-formoterol, TgAAT, cilomilast and roflumilast.

Non-limiting examples of therapeutic agents for HCV with which acompound of Formula (I) can be combined include the following:Interferon-alpha-2a, Interferon-alpha-2b, Interferon-alpha con 1,Interferon-alpha-n1, pegylated interferon-alpha-2a, pegylatedinterferon-alpha-2b, ribavirin, peginterferon alfa-2b+ribavirin,ursodeoxycholic acid, glycyrrhizic acid, thymalfasin, Maxamine, VX-497and any compounds that are used to treat HCV through intervention withthe following targets: HCV polymerase, HCV protease, HCV helicase, andHCV IRES (internal ribosome entry site).

Non-limiting examples of therapeutic agents for Idiopathic PulmonaryFibrosis with which a compound of Formula (I) can be combined includethe following: prednisone, azathioprine, albuterol, colchicine,albuterol sulfate, digoxin, gamma interferon, methylprednisolone sodsucc, lorazepam, furosemide, lisinopril, nitroglycerin, spironolactone,cyclophosphamide, ipratropium bromide, actinomycin d, alteplase,fluticasone propionate, levofloxacin, metaproterenol sulfate, morphinesulfate, oxycodone HCl, potassium chloride, triamcinolone acetonide,tacrolimus anhydrous, calcium, interferon-alpha, methotrexate,mycophenolate mofetil and interferon-gamma-1β.

Non-limiting examples of therapeutic agents for myocardial infarctionwith which a compound of Formula (I) can be combined include thefollowing: aspirin, nitroglycerin, metoprolol tartrate, enoxaparinsodium, heparin sodium, clopidogrel bisulfate, carvedilol, atenolol,morphine sulfate, metoprolol succinate, warfarin sodium, lisinopril,isosorbide mononitrate, digoxin, furosemide, simvastatin, ramipril,tenecteplase, enalapril maleate, torsemide, retavase, losartanpotassium, quinapril HCl/mag carb, bumetanide, alteplase, enalaprilat,amiodarone hydrochloride, tirofiban HCl m-hydrate, diltiazemhydrochloride, captopril, irbesartan, valsartan, propranololhydrochloride, fosinopril sodium, lidocaine hydrochloride, eptifibatide,cefazolin sodium, atropine sulfate, aminocaproic acid, spironolactone,interferon, sotalol hydrochloride, potassium chloride, docusate sodium,dobutamine HCl, alprazolam, pravastatin sodium, atorvastatin calcium,midazolam hydrochloride, meperidine hydrochloride, isosorbide dinitrate,epinephrine, dopamine hydrochloride, bivalirudin, rosuvastatin,ezetimibe/simvastatin, avasimibe, and cariporide.

Non-limiting examples of therapeutic agents for psoriasis with which acompound of Formula (I) can be combined include the following:calcipotriene, clobetasol propionate, triamcinolone acetonide,halobetasol propionate, tazarotene, methotrexate, fluocinonide,betamethasone diprop augmented, fluocinolone acetonide, acitretin, tarshampoo, betamethasone valerate, mometasone furoate, ketoconazole,pramoxine/fluocinolone, hydrocortisone valerate, flurandrenolide, urea,betamethasone, clobetasol propionate/emoll, fluticasone propionate,azithromycin, hydrocortisone, moisturizing formula, folic acid,desonide, pimecrolimus, coal tar, diflorasone diacetate, etanerceptfolate, lactic acid, methoxsalen, hc/bismuth subgal/znox/resor,methylprednisolone acetate, prednisone, sunscreen, halcinonide,salicylic acid, anthralin, clocortolone pivalate, coal extract, coaltar/salicylic acid, coal tar/salicylic acid/sulfur, desoximetasone,diazepam, emollient, fluocinonide/emollient, mineral oil/castoroil/nalact, mineral oil/peanut oil, petroleum/isopropyl myristate,psoralen, salicylic acid, soap/tribromsalan, thimerosal/boric acid,celecoxib, infliximab, cyclosporine, alefacept, efalizumab, tacrolimus,pimecrolimus, PUVA, UVB, and sulfasalazine.

Non-limiting examples of therapeutic agents for psoriatic arthritis withwhich a compound of Formula (I) can be combined include the following:D2E7 (U.S. Pat. No. 6,090,382; HUMIRA®), methotrexate, etanercept,rofecoxib, celecoxib, folic acid, sulfasalazine, naproxen, leflunomide,methylprednisolone acetate, indomethacin, hydroxychloroquine sulfate,prednisone, sulindac, betamethasone diprop augmented, infliximab,methotrexate, folate, triamcinolone acetonide, diclofenac,dimethylsulfoxide, piroxicam, diclofenac sodium, ketoprofen, meloxicam,methylprednisolone, nabumetone, tolmetin sodium, calcipotriene,cyclosporine, diclofenac sodium/misoprostol, fluocinonide, glucosaminesulfate, gold sodium thiomalate, hydrocodone bitartrate/apap, ibuprofen,risedronate sodium, sulfadiazine, thioguanine, valdecoxib, alefacept andefalizumab.

Non-limiting examples of therapeutic agents for restenosis with which acompound of Formula (I) can be combined include the following:sirolimus, paclitaxel, everolimus, tacrolimus, ABT-578, andacetaminophen.

Non-limiting examples of therapeutic agents for sciatica with which acompound of Formula (I) can be combined include the following:hydrocodone bitartrate/apap, rofecoxib, cyclobenzaprine HCl,methylprednisolone, naproxen, ibuprofen, oxycodone HCl/acetaminophen,celecoxib, valdecoxib, methylprednisolone acetate, prednisone, codeinephosphate/apap, tramadol HCl/acetaminophen, metaxalone, meloxicam,methocarbamol, lidocaine hydrochloride, diclofenac sodium, gabapentin,dexamethasone, carisoprodol, ketorolac tromethamine, indomethacin,acetaminophen, diazepam, nabumetone, oxycodone HCl, tizanidine HCl,diclofenac sodium/misoprostol, propoxyphene napsylate/apap,asa/oxycod/oxycodone ter, ibuprofen/hydrocodone bit, tramadol HCl,etodolac, propoxyphene HCl, amitriptyline HCl, carisoprodol/codeinephos/asa, morphine sulfate, multivitamins, naproxen sodium, orphenadrinecitrate, and temazepam.

Preferred examples of therapeutic agents for SLE (Lupus) with which acompound of Formula (I) can be combined include the following: NSAIDS,for example, diclofenac, naproxen, ibuprofen, piroxicam, indomethacin;COX2 inhibitors, for example, celecoxib, rofecoxib, valdecoxib;anti-malarials, for example, hydroxychloroquine; steroids, for example,prednisone, prednisolone, budenoside, dexamethasone; cytotoxics, forexample, azathioprine, cyclophosphamide, mycophenolate mofetil,methotrexate; inhibitors of PDE4 or purine synthesis inhibitor, forexample Cellcept®. A compound of Formula (I) may also be combined withagents such as sulfasalazine, 5-aminosalicylic acid, olsalazine, Imuran®and agents which interfere with synthesis, production or action ofproinflammatory cytokines such as IL-1, for example, caspase inhibitorslike IL-1β converting enzyme inhibitors and IL-1ra. A compound ofFormula (I) may also be used with T cell signaling inhibitors, forexample, tyrosine kinase inhibitors; or molecules that target T cellactivation molecules, for example, CTLA-4-IgG or anti-B7 familyantibodies, anti-PD-1 family antibodies. A compound of Formula (I) canbe combined with IL-11 or anti-cytokine antibodies, for example,fonotolizumab (anti-IFNg antibody), or anti-receptor receptorantibodies, for example, anti-IL-6 receptor antibody and antibodies toB-cell surface molecules. A compound of Formula (I) may also be usedwith LJP 394 (abetimus), agents that deplete or inactivate B-cells, forexample, Rituximab (anti-CD20 antibody), lymphostat-B (anti-BlySantibody), TNF antagonists, for example, anti-TNF antibodies, D2E7 (U.S.Pat. No. 6,090,382; HUMIRA®), CA2 (REMICADE™), CDP 571, TNFR-Igconstructs, (p75TNFRIgG (ENBREL™) and p55TNFRIgG (LENERCEPT™)).

In this invention, the following definitions are applicable:

A “therapeutically effective amount” is an amount of a compound ofFormula (I) or a combination of two or more such compounds, whichinhibits, totally or partially, the progression of the condition oralleviates, at least partially, one or more symptoms of the condition. Atherapeutically effective amount can also be an amount which isprophylactically effective. The amount which is therapeuticallyeffective will depend upon the patient's size and gender, the conditionto be treated, the severity of the condition and the result sought. Fora given patient, a therapeutically effective amount can be determined bymethods known to those of skill in the art.

“Physiologically acceptable salts” refers to those salts which retainthe biological effectiveness and properties of the free bases and whichare obtained by reaction with inorganic acids, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acidor organic acids such as sulfonic acid, carboxylic acid, organicphosphoric acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid, citric acid, fumaric acid, maleic acid, succinicacid, benzoic acid, salicylic acid, lactic acid, tartaric acid (e.g. (+)or (−)-tartaric acid or mixtures thereof), amino acids (e.g. (+) or(−)-amino acids or mixtures thereof), and the like. These salts can beprepared by methods known to those skilled in the art.

Certain compounds of Formula (I) which have acidic substituents mayexist as salts with pharmaceutically acceptable bases. The presentinvention includes such salts. Examples of such salts include sodiumsalts, potassium salts, lysine salts and arginine salts. These salts maybe prepared by methods known to those skilled in the art.

Certain compounds of Formula (I) and their salts may exist in more thanone crystal form and the present invention includes each crystal formand mixtures thereof.

Certain compounds of Formula (I) and their salts may also exist in theform of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Certain compounds of Formula (I) may contain one or more chiral centers,and exist in different optically active forms. When compounds of Formula(I) contain one chiral center, the compounds exist in two enantiomericforms and the present invention includes both enantiomers and mixturesof enantiomers, such as racemic mixtures. The enantiomers may beresolved by methods known to those skilled in the art, for example byformation of diastereoisomeric salts which may be separated, forexample, by crystallization; formation of diastereoisomeric derivativesor complexes which may be separated, for example, by crystallization,gas-liquid or liquid chromatography; selective reaction of oneenantiomer with an enantiomer-specific reagent, for example enzymaticesterification; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support for example silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where the desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step is required to liberate the desired enantiomeric form.Alternatively, specific enantiomers may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer into the other by asymmetrictransformation.

When a compound of Formula (I) contains more than one chiral center, itmay exist in diastereoisomeric forms. The diastereoisomeric compoundsmay be separated by methods known to those skilled in the art, forexample chromatography or crystallization and the individual enantiomersmay be separated as described above. The present invention includes eachdiastereoisomer of compounds of Formula (I) and mixtures thereof.

Certain compounds of formula I may exist in different tautomeric formsor as different geometric isomers, and the present invention includeseach tautomer and/or geometric isomer of compounds of Formula (I) andmixtures thereof.

Certain compounds of Formula (I) may exist in different stableconformational forms which may be separable. Torsional asymmetry due torestricted rotation about an asymmetric single bond, for example becauseof steric hindrance or ring strain, may permit separation of differentconformers. The present invention includes each conformational isomer ofcompounds of Formula (I) and mixtures thereof.

Certain compounds of Formula (I) may exist in zwitterionic form and thepresent invention includes each zwitterionic form of compounds ofFormula (I) and mixtures thereof.

As used herein the term “pro-drug” refers to an agent which is convertedinto the parent drug in vivo by some physiological chemical process(e.g., a pro-drug on being brought to the physiological pH is convertedto the desired drug form). Pro-drugs are often useful because, in somesituations, they may be easier to administer than the parent drug. Theymay, for instance, be bioavailable by oral administration whereas theparent drug is not. The pro-drug may also have improved solubility inpharmacological compositions over the parent drug. An example, withoutlimitation, of a pro-drug would be a compound of the present inventionwherein it is administered as an ester (the “pro-drug”) to facilitatetransmittal across a cell membrane where water solubility is notbeneficial, but then it is metabolically hydrolyzed to the carboxylicacid once inside the cell where water solubility is beneficial

Pro-drugs have many useful properties. For example, a pro-drug may bemore water soluble than the ultimate drug, thereby facilitatingintravenous administration of the drug. A pro-drug may also have ahigher level of oral bioavailability than the ultimate drug. Afteradministration, the pro-drug is enzymatically or chemically cleaved todeliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs upon cleavage release the corresponding free acid,and such hydrolyzable ester-forming residues of the compounds of thisinvention include but are not limited to carboxylic acid substituents(e.g., —(CH₂)C(O)H or a moiety that contains a carboxylic acid) whereinthe free hydrogen is replaced by (C₁-C₄)alkyl,(C₂-C₁₂)alkanoyloxymethyl, (C₄-C₉)1-(alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl(such as (3-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

Other exemplary pro-drugs release an alcohol of Formula (I) wherein thefree hydrogen of the hydroxyl substituent (e.g., R¹ contains hydroxyl)is replaced by (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylamino-methyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylactyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl wherein said α-aminoacyl moieties areindependently any of the naturally occurring L-amino acids found inproteins, P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radicalresulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

The term “heterocyclic” or “heterocyclyl”, as used herein, includenon-aromatic, ring systems, including, but not limited to, monocyclic,bicyclic and tricyclic rings, which can be completely saturated or whichcan contain one or more units of unsaturation, (for the avoidance ofdoubt, the degree of unsaturation does not result in an aromatic ringsystem) and have 3 to 12 atoms including at least one heteroatom, suchas nitrogen, oxygen, or sulfur. For purposes of exemplification, whichshould not be construed as limiting the scope of this invention, thefollowing are examples of heterocyclic rings: azepinyl, azetidinyl,morpholinyl, oxopiperidinyl, oxopyrrolidinyl, piperazinyl, piperidinyl,pyrrolidinyl, quinicludinyl, thiomorpholinyl, tetrahydropyranyl,tetrahydrofuranyl, 5,6,7,8-tetrahydro[1,6]naphtyridinyl,decahydroisoquinolinyl and 2,3-dihydro-1H-isoindolyl.

The term “heteroaryl” as used herein, include aromatic ring systems,including, but not limited to, monocyclic, bicyclic and tricyclic rings,and have 3 to 12 atoms including at least one heteroatom, such asnitrogen, oxygen, or sulfur. For purposes of exemplification, whichshould not be construed as limiting the scope of this invention:azaindolyl, benzo[b]thienyl, benzimidazolyl, benzofuranyl, benzoxazolyl,benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, furanyl, imidazolyl,imidazopyridyl, indolyl, indolinyl, indazolyl, isoindolinyl, isoxazole,isothiazolyl, oxadiazolyl, oxazolyl, purinyl, pyranyl, pyrazinyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrrolyl, pyrrolo[2,3-d]pyrimidinyl,pyrazolo[3,4-d]pyrimidinyl, quinolinyl, quinazolinyl, triazolyl,thiazolyl, thiophenyl, tetrahydroindolyl, tetrazolyl, thiadiazolyl,thienyl, thiomorpholinyl or tropanyl.

When the term “substituted heterocyclic” (or heterocyclyl) or“substituted heteroaryl” is used, what is meant is that the heterocyclicgroup is substituted with one or more substituents that can be made byone of ordinary skill in the art and results in a molecule that is aCCR2 antagonist. For purposes of exemplification, which should not beconstrued as limiting the scope of this invention, preferredsubstituents for the heterocycle of this invention are eachindependently selected from the optionally substituted group consistingof alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl,alkoxycarbonylheterocycloalkoxy, alkyl, alkylcarbonyl, alkylester,alkyl-O—C(O)—, alkyl-heterocyclyl, alkyl-cycloalkyl, alkyl-nitrile,alkynyl, amido groups, amino, aminoalkyl, aminocarbonyl, carbonitrile,carbonylalkoxy, carboxamido, CF₃, CN, —C(O)OH, —C(O)H, —C(O)—C(CH₃)₃,—OH, —C(O)O-alkyl, —C(O)β-cycloalkyl, —C(O)O-heterocyclyl, —C(O)-alkyl,—C(O)-cycloalkyl, —C(O)-heterocyclyl, cycloalkyl, dialkylaminoalkoxy,dialkylaminocarbonylalkoxy, dialkylaminocarbonyl, halogen, heterocyclyl,a heterocycloalkyl group, heterocyclyloxy, hydroxy, hydroxyalkyl, nitro,OCF₃, oxo, phenyl, —SO₂CH₃, —SO₂CR₃, tetrazolyl, thienylalkoxy,trifluoromethylcarbonylamino, trifluoromethylsulfonamido,heterocyclylalkoxy, heterocyclyl-S(O)_(p), cycloalkyl-S(O)_(p),alkyl-S—, heterocyclyl-S, heterocycloalkyl, cycloalkylalkyl,heterocyclothio, cycloalkylthio, —Z¹⁰⁵—C(O)N(R)₂, —Z¹⁰⁵—N(R)—C(O)—Z²⁰⁰,—Z¹⁰⁵—N(R)—S(O)₂—Z²⁰⁰, —Z¹⁰⁵—N(R)—C(O)—N(R)—Z²⁰⁰, —N(R)—C(O)R,—N(R)—C(O)OR, OR—C(O)-heterocyclyl-OR, R_(c) and —CH₂OR_(c);

-   -   wherein R₃ is C₁-C₄ alkyl, C₃-C₆ cycloalkyl or phenyl;    -   wherein p is 0, 1 or 2;    -   where R_(c) for each occurrence is independently hydrogen,        optionally substituted alkyl, optionally substituted aryl,        —(C₁-C₆)—NR_(d)R_(e), -E-(CH₂)_(t)—NR_(d)R_(e),        -E-(CH₂)_(t)—O-alkyl, -E-(CH₂)_(t)—S-alkyl, or -E-(CH₂)_(t)—OH;        -   wherein t is an integer from about 1 to about 6;    -   Z¹⁰⁵ for each occurrence is independently a covalent bond,        alkyl, alkenyl or alkynyl; and    -   Z²⁰⁰ for each occurrence is independently selected from an        optionally substituted group selected from the group consisting        of alkyl, alkenyl, alkynyl, phenyl, alkyl-phenyl, alkenyl-phenyl        or alkynyl-phenyl;    -   E is a direct bond, O, S, S(O), S(O)₂, or NR_(f), wherein R_(f)        is H or alkyl and R_(d) and R_(e) are independently H, alkyl,        alkanoyl or SO₂-alkyl; or R_(d), R_(e) and the nitrogen atom to        which they are attached together to form a five- or six-membered        heterocyclic ring.

An “heterocycloalkyl” group, as used herein, is a heterocyclic groupthat is linked to a compound by an aliphatic group having from one toabout eight carbon atoms. For example, a heterocycloalkyl group is amorpholinomethyl group.

As used herein, “alkyl” means C₁-C₈ and includes straight chained orbranched hydrocarbons, which are completely saturated. Preferred alkylsare methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl andisomers thereof. As used herein, “alkenyl” and “alkynyl” means C₂-C₈ andincludes straight chained or branched hydrocarbons which contain one ormore units of unsaturation, one or more double bonds for alkenyl and oneor more triple bonds for alkynyl.

As used herein, aromatic groups (or aryl groups) include aromaticcarbocyclic ring systems (e.g. phenyl and cyclopentyldienyl) and fusedpolycyclic aromatic ring systems (e.g. naphthyl, biphenylenyl and1,2,3,4-tetrahydronaphthyl).

As used herein, cycloalkyl means C₃-C₁₂ monocyclic or multicyclic (e.g.,bicyclic, tricyclic, etc.) hydrocarbons that is completely saturated orhas one or more unsaturated bonds but does not amount to an aromaticgroup. Preferred examples of a cycloalkyl group are cyclopropyl,cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl and cyclohexenyl.

As used herein, many moieties or substituents are termed as being either“substituted” or “optionally substituted”. When a moiety is modified byone of these terms, unless otherwise noted, it denotes that any portionof the moiety that is known to one skilled in the art as being availablefor substitution can be substituted, which includes one or moresubstituents, where if more than one substituent then each substituentis independently selected. Such means for substitution are well-known inthe art and/or taught by the instant disclosure. For purposes ofexemplification, which should not be construed as limiting the scope ofthis invention, some examples of groups that are substituents are:alkenyl groups, alkoxy group (which itself can be substituted, such as—O—C₁-C₆-alkyl-OR, —O—C₁-C₆-alkyl-N(R)₂, and OCF₃), alkoxyalkoxy,alkoxycarbonyl, alkoxycarbonylpiperidinyl-alkoxy, alkyl groups (whichitself can also be substituted, such as —C₁-C₆-alkyl-OR,—C₁-C₆-alkyl-N(R)₂, and —CF₃), alkylamino, alkylcarbonyl, alkylester,alkylnitrile, alkylsulfonyl, amino, aminoalkoxy, CF₃, COH, COON, CN,cycloalkyl, dialkylamino, dialkylaminoalkoxy, dialkylaminocarbonyl,dialkylaminocarbonylalkoxy, dialkylaminosulfonyl, esters (—C(O)—OR,where R is groups such as alkyl, heterocycloalkyl (which can besubstituted), heterocyclyl, etc., which can be substituted), halogen orhalo group (F, Cl, Br, I), hydroxy, morpholinoalkoxy, morpholinoalkyl,nitro, oxo, OCF₃, optionally substituted phenyl, S(O)₂CH₃, S(O)₂CF₃, andsulfonyl, N-alkylamino or N,N-dialkylamino (in which the alkyl groupscan also be substituted).

One or more compounds of this invention can be administered to a humanpatient by themselves or in pharmaceutical compositions where they aremixed with biologically suitable carriers or excipient(s) at doses totreat or ameliorate a disease or condition as described herein. Mixturesof these compounds can also be administered to the patient as a simplemixture or in suitable formulated pharmaceutical compositions. Atherapeutically effective dose refers to that amount of the compound orcompounds sufficient to result in the prevention or attenuation of adisease or condition as described herein. Techniques for formulation andadministration of the compounds of the instant application may be foundin references well known to one of ordinary skill in the art, such as“Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, Pa.,latest edition.

Suitable routes of administration may, for example, include oral,eyedrop, rectal, transmucosal, topical, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections.

Alternatively, one may administer the compound in a local rather than asystemic manner, for example, via injection of the compound directlyinto an edematous site, often in a depot or sustained releaseformulation.

Furthermore, one may administer the drug in a targeted drug deliverysystem, for example, in a liposome coated with endothelial cell-specificantibody.

The pharmaceutical compositions of the present invention may bemanufactured in a manner that is itself known, e.g., by means ofconventional mixing, dissolving, granulating, dragee-making, levigating,emulsifying, encapsulating, entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants appropriate to the barrier to bepermeated are used in the formulation. Such penetrants are generallyknown in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients are, in particular,fillers such as sugars, including lactose, sucrose, mannitol, orsorbitol; cellulose preparations such as, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired,disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added. All formulations fororal administration should be in dosages suitable for suchadministration.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration byinjection, e.g. bolus injection or continuous infusion. Formulations forinjection may be presented in unit dosage form, e.g. in ampoules or inmulti-dose containers, with an added preservative. The compositions maytake such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly or by intramuscular injection). Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

An example of a pharmaceutical carrier for the hydrophobic compounds ofthe invention is a cosolvent system comprising benzyl alcohol, anonpolar surfactant, a water-miscible organic polymer, and an aqueousphase. The cosolvent system may be the VPD co-solvent system. VPD is asolution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactantpolysorbate 80, and 65% w/v polyethylene glycol 300, made up to volumein absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPDdiluted 1:1 with a 5% dextrose in water solution. This co-solvent systemdissolves hydrophobic compounds well, and itself produces low toxicityupon systemic administration. Naturally, the proportions of a co-solventsystem may be varied considerably without destroying its solubility andtoxicity characteristics. Furthermore, the identity of the co-solventcomponents may be varied: for example, other low-toxicity nonpolarsurfactants may be used instead of polysorbate 80; the fraction size ofpolyethylene glycol may be varied; other biocompatible polymers mayreplace polyethylene glycol, e.g. polyvinyl pyrrolidone; and othersugars or polysaccharides may substitute for dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are well knownexamples of delivery vehicles or carriers for hydrophobic drugs. Certainorganic solvents such as dimethysulfoxide also may be employed, althoughusually at the cost of greater toxicity. Additionally, the compounds maybe delivered using a sustained-release system, such as semipermeablematrices of solid hydrophobic polymers containing the therapeutic agent.Various sustained-release materials have been established and are wellknown by those skilled in the art. Sustained-release capsules may,depending on their chemical nature, release the compounds for a fewweeks up to over 100 days. Depending on the chemical nature and thebiological stability of the therapeutic reagent, additional strategiesfor protein stabilization may be employed.

The pharmaceutical compositions also may comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

Many of the compounds of the invention may be provided as salts withpharmaceutically compatible counterions. Pharmaceutically compatiblesalts may be formed with many acids, including but not limited tohydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc.Salts tend to be more soluble in aqueous or other protonic solvents thanare the corresponding free base forms.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in aneffective amount to achieve its intended purpose. More specifically, atherapeutically effective amount means an amount effective to preventdevelopment of or to alleviate the existing symptoms of the subjectbeing treated. Determination of the effective amounts is well within thecapability of those skilled in the art.

For any compound used in a method of the present invention, thetherapeutically effective dose can be estimated initially from cellularassays. For example, a dose can be formulated in cellular and animalmodels to achieve a circulating concentration range that includes theIC₅₀ as determined in cellular assays (i.e., the concentration of thetest compound which achieves a half-maximal inhibition of a given CCR2activity). In some cases it is appropriate to determine the IC₅₀ in thepresence of 3 to 5% serum albumin since such a determinationapproximates the binding effects of plasma protein on the compound. Suchinformation can be used to more accurately determine useful doses inhumans. Further, the most preferred compounds for systemicadministration effectively inhibit CCR2 signaling in intact cells atlevels that are safely achievable in plasma.

A therapeutically effective dose refers to that amount of the compoundthat results in amelioration of symptoms in a patient. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the maximum tolerated dose (MTD) and the ED₅₀(effective dose for 50% maximal response). The dose ratio between toxicand therapeutic effects is the therapeutic index and it can be expressedas the ratio between MTD and ED₅₀. Compounds which exhibit hightherapeutic indices are preferred. The data obtained from these cellculture assays and animal studies can be used in formulating a range ofdosage for use in humans. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the ED₅₀ withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition. (Seee.g. Fingl et al., 1975, in “The Pharmacological Basis of Therapeutics”,Ch. 1 p 1). In the treatment of crises, the administration of an acutebolus or an infusion approaching the MTD may be required to obtain arapid response.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain theCCR2 modulating effects, or minimal effective concentration (MEC). TheMEC will vary for each compound but can be estimated from in vitro data;e.g. the concentration necessary to achieve 50-90% inhibition of CCR2using the assays described herein. Dosages necessary to achieve the MECwill depend on individual characteristics and route of administration.However, HPLC assays or bioassays can be used to determine plasmaconcentrations.

Dosage intervals can also be determined using the MEC value. Compoundsshould be administered using a regimen which maintains plasma levelsabove the MEC for 10-90% of the time, preferably between 30-90% and mostpreferably between 50-90% until the desired amelioration of symptoms isachieved. In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

The compositions may, if desired, be presented in a pack or dispenserdevice which may contain one or more unit dosage forms containing theactive ingredient. The pack may for example comprise metal or plasticfoil, such as a blister pack. The pack or dispenser device may beaccompanied by instructions for administration. Compositions comprisinga compound of the invention formulated in a compatible pharmaceuticalcarrier may also be prepared, placed in an appropriate container, andlabelled for treatment of an indicated condition.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

The use of compounds of the present invention in the manufacture ofpharmaceutical compositions is illustrated by the following description.In this description the term “active compound” denotes any compound ofthe invention but particularly any compound which is the final productof one of the preceding Examples.

a) Capsules

In the preparation of capsules, 10 parts by weight of active compoundand 240 parts by weight of lactose can be de-aggregated and blended. Themixture can be filled into hard gelatin capsules, each capsulecontaining a unit dose or part of a unit dose of active compound.

b) Tablets

Tablets can be prepared, for example, from the following ingredients.

Parts by weight

Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10Magnesium stearate 3

The active compound, the lactose and some of the starch can bede-aggregated, blended and the resulting mixture can be granulated witha solution of the polyvinylpyrrolidone in ethanol. The dry granulate canbe blended with the magnesium stearate and the rest of the starch. Themixture is then compressed in a tabletting machine to give tablets eachcontaining a unit dose or a part of a unit dose of active compound.

c) Enteric Coated Tablets

Tablets can be prepared by the method described in (b) above. Thetablets can be enteric coated in a conventional manner using a solutionof 20% cellulose acetate phthalate and 3% diethyl phthalate inethanol:dichloromethane (1:1).

d) Suppositories

In the preparation of suppositories, for example, 100 parts by weight ofactive compound can be incorporated in 1300 parts by weight oftriglyceride suppository base and the mixture formed into suppositorieseach containing a therapeutically effective amount of active ingredient.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients. For example, the compounds of this invention can beadministered in combination with another therapeutic agent that is knownto treat a disease or condition described herein. For example, with oneor more additional pharmaceutical agents that inhibit or prevent theproduction of VEGF or angiopoietins, attenuate intracellular responsesto VEGF or angiopoietins, block intracellular signal transduction,inhibit vascular hyperpermeability, reduce inflammation, or inhibit orprevent the formation of edema or neovascularization. The compounds ofthe invention can be administered prior to, subsequent to orsimultaneously with the additional pharmaceutical agent, whichevercourse of administration is appropriate. The additional pharmaceuticalagents include, but are not limited to, anti-edemic steroids, NSAIDS,ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines,PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthaseinhibitors, Akt/PTB inhibitors, IGF-1R inhibitors, PKC inhibitors, PI3kinase inhibitors, calcineurin inhibitors and immunosuppressants. Thecompounds of the invention and the additional pharmaceutical agents acteither additively or synergistically. Thus, the administration of such acombination of substances that inhibit angiogenesis, vascularhyperpermeability and/or inhibit the formation of edema can providegreater relief from the deletrious effects of a hyperproliferativedisorder, angiogenesis, vascular hyperpermeability or edema than theadministration of either substance alone. In the treatment of malignantdisorders combinations with antiproliferative or cytotoxicchemotherapies or radiation are included in the scope of the presentinvention.

The present invention also comprises the use of a compound of Formula(I) as a medicament.

A further aspect of the present invention provides the use of a compoundof Formula (I) or a salt thereof in the manufacture of a medicament fortreating vascular hyperpermeability, angiogenesis-dependent disorders,proliferative diseases and/or disorders of the immune system in mammals,particularly human beings.

The present invention also provides a method of treating vascularhyperpermeability, inappropriate neovascularization, proliferativediseases and/or disorders of the immune system which comprises theadministration of a therapeutically effective amount of a compound ofFormula (I) to a mammal, particularly a human being, in need thereof.

The teachings of all references, including journal articles, patents andpublished patent applications, are incorporated herein by reference intheir entirety.

Enzyme Assays

Assays for Screening Compounds of Formula (I)

The in vitro potency of compounds in antagonizing CCR2 discussed hereinor described in the art may be determined by the procedures detailedbelow.

CHO cells expressing either human CCR2b or murine CCR2 were generated asfollows. cDNA for human CCR2b (cloned from human blood) and murine CCR2(cloned from mouse brain or PEC) were cloned into plasmid pcDNA3.1 (fromInvitrogen). The resulting plasmids were separately transfected into CHOcells expressing human Ga16 (from Molecular Devices). Sequences of thetransfected CCR2 open reading frames in the resulting cell lines wereidentical to human CCR2b (NM_(—)000648) and mouse CCR2 (NM_(—)00915.1)respectively.

Inhibition of MCP-1 Binding to hCCR2 or mCCR2

Radioligand binding assays were performed in CHO cells expressing eitherhuman CCR2B and the Gα₁₆ coupling protein or murine CCR2 and the Gα₁₆coupling protein. All compounds were dissolved in DMSO and assays run ata final DMSO concentration of 1% (v/v). [¹²⁵I]-labeled human and murineMCP-1 was purchased from PerkinElmer. Unlabeled human and murine MCP-1were purchased from Peprotech. Assays with cells expressing human CCR2Bwere performed with human MCP-1, while assays with cells expressingmurine CCR2 were performed with murine MCP-1.

Compounds are serially diluted in DMSO before diluting into assay buffer(25 mM HEPES, pH 7.4, 5 mM MgCl₂, 1 mM CaCl₂, 0.5% BSA) with cryopreserved CHO cells expressing either human CCR2B and the Gα₁₆ couplingprotein or murine CCR2 and the Gα₁₆ coupling protein (50×10³/well) and[¹²⁵I]-MCP-1 (50 pM for human CCR2, 100 pM for murine CCR2). Thereaction was incubated at room temperature for 90 minutes beforetransferring to GF/C filter plates (PerkinElmer) pre-treated with 0.3%polyethyleneimine for 2 hours at 4° C. The filter plates are washed sixtimes with ice cold wash buffer (25 mM HEPES, pH 7.4, 5 mM MgCl₂, 1 mMCaCl₂, 500 mM NaCl) and dried before adding 50 ul/well Microscint toeach well. Plates are counted on Packard Topcount scintillation counterwhere background binding is determined 100 nM MCP-1 and control totalbinding determined by addition of DMSO in place of the test compound.The radioactivity values (cpm) were used to calculate the percentinhibition at a given compound concentration and the data fit to asigmoidal curve in a semi-log plot to determine IC₅₀ values.

Inhibition of MCP-1-Induced Intracellular Calcium Release in CellsExpressing hCCR2 or mCCR2

Calcium flux assays were performed in CHO cells expressing either humanCCR2B and the Gα₁₆ coupling protein or murine CCR2 and the Gα₁₆ couplingprotein. All compounds were dissolved in DMSO and assays run at a finalDMSO concentration of 1% (v/v). Human and murine MCP-1 were purchasedfrom Peprotech and used at a final assay concentration of 10 nM. Assayswith cells expressing human CCR2B were performed with human MCP-1, whileassays with cells expressing murine CCR2 were performed with murineMCP-1.

Briefly, cells were cultured overnight in a microtiter plate at 40,000per well. The next day, the resultant adherent cells were incubated inassay buffer (20 mM HEPES pH 7.4, 0.1% bovine serum albumin, and 2.5 mMProbenocid in Hank's Buffered Saline Solution) containing 5 μg/ml μMFluo-4 dye (Molecular Probes) at room temperature for 60 min. Thedye-containing assay buffer was removed and replace by assay bufferwithout dye. Calcium flux assays were performed on a FLIPR Tetrainstrument (Molecular Devices) by adding compound to the cells followedby addition of MCP-1 and measuring the change in fluorescence as afunction of time. Maximal and minimal values for fluorescence weredetermined using 100 nM MCP-1 and buffer addition, respectively.Fluorescence values were used to calculate the percent inhibition at agiven compound concentration and the data fit to a sigmoidal curve in asemi-log plot to determine IC₅₀ values.

Compounds of the invention may be prepared using the synthetic schemeillustrated in Scheme A. Starting materials are commercially availableor may be prepared by the procedures described herein or by proceduresthat would be well known to one skilled in the art of organic chemistry.The variables used in the Scheme are as defined herein or as in theclaims. General procedures are noted in parentheses.

A method for preparing 2-aminooctahydropentalene-3a-carboxamidecompounds of the invention is illustrated in Scheme A. In Scheme A, stepi, a suitably substituted 4,5,6,6a-tetrahydropentalen-2(1H)-one 1 ishydrogenated, typically in the presence of hydrogen and a metal catalyst(such as Pd/C) in an organic solvent (such as EtOH). Ester hydrolysis,typically conducted in an organic solvent such as THF treated withaqueous sodium hydroxide, followed by amide coupling with a suitableamine (step ii) provides intermediate 3. The amide coupling reaction ofthe ketone with a suitably substituted amine is typically run in anorganic solvent (such as DMA) in the presence of a base (such as Et₃N),and activating agent (such as HOBT), and a coupling reagent (such asPS-carbodiimide) at ambient temperature. The reductive aminationreaction (steps iii or iv) is typically conducted in an organic solvent(such as 1,2-dichloroethane) at room temperature with sodiumtriacetoxyborohydride and acetic acid. Ester 4 is functionalizedutilizing chemistry similar to that described above in step (ii) toafford product 5. Product 5 can then be isolated and purified usingstandard techniques (such as crystallization, flash columnchromatography, or reverse-phase liquid chromatography).

ABBREVIATIONS

DCE Dichloroethane DCM Dichloromethane DMA N,N-Dimethylacetamide DMSODimethyl sulfoxide Et₃N Triethylamine Et₂O Diethyl ether HOBT1-Hydroxybenzotriazole HPLC High Performance Liquid Chromatography MeCNAcetonitrile MeOH Methanol MgSO₄ Magnesium sulfate i-PrOH 2-Propanoln-PrOH 1-Propanol PS-carbodiimide N-Cyclohexylcarbodiimide-N′-propyloxymethyl polystyrene RP Reverse Phase R_(t) Retention time THFTetrahydrofuranSynthetic DetailsAnalytical data are included either in the illustrations of the generalprocedures or in the tables of examples. Unless otherwise stated, all ¹Hor ¹³C NMR data were collected on a Varian Mercury Plus 400 MHzinstrument; chemical shifts are quoted in parts per million (ppm). Highpressure liquid chromatography (HPLC) analytical data are eitherdetailed within the experimental or referenced to the table of HPLCconditions, using the lower case method letter, in Table A.

TABLE A List of HPLC methods HPLC Conditions Unless indicated otherwisemobile phase A was 10 mM ammonium acetate, mobile phase B was HPLC gradeMethod acetonitrile. a 5-95% B over 3.7 min with a hold at 95% B for 1min (1.3 mL/min flow rate). 4.6 × 50 mm Waters Atlantis dC18 column (5μm particles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as pos/neg electrosprayionization. b 5-60% B over 1.5 min then 60-95% B to 2.5 min with a holdat 95% B for 1.2 min (1.3 mL/min flow rate). 4.6 × 30 mm Vydac GenesisC8 column (4 μm particles). Detection methods are diode array (DAD) andevaporative light scattering (ELSD) detection as well as pos/negelectrospray ionization. c 5-95% B in 3.7 min with a hold at 95% B for 1min (1.3 mL/min flow rate). 4.6 × 50 mm Waters Atlantis dC18 column (5μm particles). Detection methods are diode array (DAD) and evaporativelight scattering (ELSD) detection as well as pos/neg atmosphericpressure chemical ionization (APCI) d 10 to 70% gradient over 19 min ofisopropanol in heptane with 0.2% diethylamine on Daicel AD-H column (4.6× 250 mm) at 35 deg C. and 1.0 mL/min flow rate (UV wavelength monitored= 265 nm)

GENERAL PROCEDURES AND EXAMPLES

The general synthetic schemes that were utilized to construct themajority of compounds disclosed in this application are described belowin Schemes 1-2.

List of General Procedures:General Procedure A: Hydrolysis of an ester to a carboxylic acid.General Procedure B: Formation of an amide by peptide coupling.General Procedure C: Formation of an amine by reductive amination.Intermediates:

Methyl 5-oxo-1,2,3,3a,4,5-hexahydropentalene-3a-carboxylate was preparedvia the route detailed in J. Org. Chem. 1981, 46, 2816-2818.

3-Trifluoromethyl-5,6,7,8-tetrahydro-[1,6]naphthyridine was prepared viathe route detailed in WO 2005/044264.

Methyl 2-oxooctahydropentalene-3a-carboxylate: Methyl5-oxo-1,2,3,3a,4,5-hexahydropentalene-3a-carboxylate (2.5 g, 12.8 mmol)in ethanol (25 mL) was purged with nitrogen for about 10 minutes withstirring. Palladium on carbon (0.043 g, 20 mol %) was added and thereaction vessel was purged with nitrogen for about 10 minutes. The flowof nitrogen was stopped and the flask was flushed with hydrogen. Thereaction mixture was stirred overnight under an atmosphere of hydrogen.The flask was flushed with nitrogen for about 20 minutes. The reactionmixture was passed through a pad of Celite® and the filtrate wasconcentrated in vacuo. The residue was purified by flash columnchromatography (eluting with 25% ethyl acetate/heptane) to afford ethyl2-oxooctahydropentalene-3a-carboxylate (2.04 g, 10.4 mmol, 81%).

The general procedure letter codes constitute a synthetic route to thefinal product. A worked example of how the route is determined is givenbelow using the synthesis of Preparation #3 as a non-limitingillustration. Preparation #3([2-(2,4-Dimethyl-benzylamino)-hexahydro-pentalen-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone)was prepared from2-(2,4-dimethylbenzylamino)octahydropentalene-3a-carboxylic acid and3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-napthyridine using GeneralProcedure B, as represented in the following synthetic scheme.

The acid was prepared using the route (C, A). This translates into thefollowing sequence, where the acid starting material used in generalprocedure B is the product of the following procedures C and A, in thegiven order.

General Procedure A: Hydrolysis of an Ester to a Carboxylic Acid.

To a mixture of an ester (1 equivalent) in an organic solvent(preferably THF) is added an aqueous solution of inorganic hydroxide(1-30 equivalents, preferably about 10 equivalents) (preferably sodiumhydroxide). The reaction mixture is stirred at about 20-50° C.(preferably at about 25° C.) for about 1-24 h (preferably about 18 h).The solvent is removed under reduced pressure and the residue ispartitioned between an organic solvent (preferably DCM) and water thenseparated and dried over dessicant (preferably magnesium sulfate) andconcentrated. The crude product can be further purified bychromatography or crystallization or used without additionalpurification.

Illustration of General Procedure A

Preparation #12-(4-Phenyl-piperidin-1-yl)-hexahydro-pentalene-3a-carboxylic acid

To a solution of ethyl2-(4-phenylpiperidin-1-yl)octahydropentalene-3a-carboxylate (1.85 g,5.42 mmol) in THF (35 mL) was added a solution of sodium hydroxide (2.16g, 54.2 mmol) in water (35 mL). The reaction mixture was stirred atambient temperature for about 18 h. The solvent was removed underreduced pressure and the crude product was extracted into DCM (3×20 mL).The combined organic phases were washed with water (3×50 mL) and driedover MgSO₄. Concentration in vacuo gave2-(4-phenyl-piperidin-1-yl)-hexahydro-pentalene-3a-carboxylic acid (1.70g) that was used in the next step without further purification.

General Procedure B: Formation of an Amide by Peptide Coupling.

A mixture of an acid (1 equivalent), a suitably substituted amine (1-5equivalents, preferably 1 equivalent), a coupling reagent (1-10equivalents, preferably 1.5 equivalents, preferably PS-carbodiimide), anactivating reagent (1-3 equivalents, preferably 1 equivalent, preferablyHOBT) and a base (1-10 equivalents, preferably 1 equivalent, preferablyEt₃N) in an organic solvent (preferably DMA) is stirred at about 20-50°C. (preferably at about 25° C.) for about 1-72 h (preferably about 48h). The resin is removed by filtration and the solvent is removed underreduced pressure. The crude product can be further purified bychromatography or crystallization.

Illustration of General Procedure B

Preparation #2{2-[(2,4-Dimethyl-benzyl)-amino]-hexahydro-pentalen-3a-yl}-(3-trifluoro-methyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone

A mixture of2-((2,4-dimethylbenzyl)(methyl)amino)octahydropentalene-3a-carboxylicacid (0.075 g, 0.25 mmol),3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (0.050 g, 0.25mmol), N-((3-(4-methylbenzyloxy)propylimino)methylene)cyclohexanamine(resin bound, 1.42 mmol/g, 0.262 g, 0.373 mmol),1H-benzo[d][1,2,3]triazol-1-ol (0.034 g, 0.25 mmol) and triethylamine(0.025 g, 0.25 mmol) in DMA (3.1 mL) was stirred at ambient temperaturefor about 48 h. The resin was removed by filtration and the solventremoved under reduced pressure. The crude material was purified byRP-HPLC to provide{2-[(2,4-dimethyl-benzyl)-methyl-amino]-hexahydro-pentalen-3a-yl}-(3-trifluoro-methyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone(0.026 g). RP-HPLC (Table A, Method b) R_(t) 1.78 min; m/z: (M+H)⁺472.

General Procedure C: Formation of an Amine by Reductive Amination.

To a solution of ketone (1 equivalent) in an organic solvent (preferablyDCE) is added an amine (1-5 equivalents, preferably 1 equivalent) andthe mixture is stirred at about 20-50° C. (preferably at about 25° C.)for about 1-72 h (preferably about 2 h) then a reducing agent (1-10equivalents, preferably about 1.5 equivalents, preferably sodiumtriacetoxyborohydride) with or without an acid additive (about 1-5equivalents, preferably about 1.5 equivalents, preferably acetic acid)are added. The mixture is then stirred at about 20-50° C. (preferably atabout 25° C.) for about 1-72 h (preferably about 18 h). The reaction isquenched by the addition of an aqueous base (preferably aqueous sodiumbicarbonate) and then partitioned with an organic solvent (preferablyDCM). The solvent is removed under reduced pressure. The crude productcan be further purified by chromatography or crystallization.

Illustration of General Procedure C

Preparation #3[2-(4-Phenyl-piperidin-1-yl)-hexahydro-pentalen-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanone

To a solution of3a-(3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-6-carbonyl)hexahydropentalen-2(1H)-one(0.175 g, 0.497 mmol) in DCE (4.3 mL) was added 4-phenylpiperidine(0.080 g, 0.50 mmol). The reaction mixture was stirred at ambienttemperature for about 2 h then sodium triacetoxyborohydide (0.158 g,0.745 mmol) and acetic acid (0.043 mL, 0.74 mmol) were added. Thereaction mixture was then stirred at ambient temperature for about 18 h.Saturated aqueous sodium bicarbonate was added to the reaction mixtureand the product was extracted into DCM (3×10 mL). The solvent wasremoved under reduced pressure and the crude material was purified byRP-HPLC to provide[2-(4-phenyl-piperidin-1-yl)-hexahydro-pentalen-3a-yl]-(3-trifluoromethyl-7,8-dihydro-5H-[1,6]naphthyridin-6-yl)-methanoneas a mixture of four diastereomers (0.075 g). RP-HPLC (Table A, Methodc) R_(t) 2.05 min; m/z: (M+H)⁺498. In addition, the diastereomers wereseparated using a two-step chiral HPLC method (Step 1: Diastereomerseparation: Isocratic using 85% heptane, 7.5% methanol, 7.5% ethanolwith 0.2% diethylamine on a Daicel OD-H column (20×250 mm) at 35 deg C.and 12 mL/min flow rate (UV wavelength monitored=265 nm). Step 2:Enantiomer separation: 10-70% gradient over 19 min of isopropanol inheptane with 0.2% diethylamine on a Daicel AD-H column (20×250 mm) at 35deg C. and 16 ml/min flow rate (UV wavelength monitored=265 nm)) toprovide the four enantiomers—the absolute configuration of each compoundwas not determined Isomer 1: RP-HPLC (Table A, Method d) R_(t) 12.66min. Isomer 2: RP-HPLC (Table A, Method d) R_(t) 13.57 min. Isomer 3:RP-HPLC (Table A, Method d) R_(t) 8.46 min Isomer 4: RP-HPLC (Table A,Method d) R_(t) 11.76 min.

TABLE 1 Examples synthesized using general procedure B m/z or ¹H NMR (d6DMSO, HPLC R_(t) 400 Amine Core Product Ex. # (Method) MHz) 3-(trifluoromethyl)- 5,6,7,8- tetrahydro-1,6- naphthyridine 2-(methyl(tetra- hydro-2H- pyran-4- yl)amino)octa- hydro- pentalene-3a-carboxylic acid (C, A)

1.1 1.57 min (b) (M + H)⁺ 452 1-(4- (trifluoromethyl) phenyl) piperazine2- (methyl(tetra- hydro-2H- pyran-4- yl)amino)octa- hydro- pentalene-3a-carboxylic acid (C, A)

1.2 1.88 min (b) (M + H)⁺ 480 2-(pyrrolidin-1- yl)ethanamine 2-(methyl(tetra- hydro-2H- pyran-4- yl)amino)octa- hydro- pentalene-3a-carboxylic acid (C, A)

1.3 0.82 min (b) (M + H)⁺ 364 3-(trifluoro- methyl)-5,6,7,8-tetrahydro-1,6- naphthyridine 2-(methyl(2- (piperidin-1- yl)ethyl)amino)octahydro- pentalene-3a- carboxylic acid (C, A)

1.4 1.45 min (b) (M + H)⁺ 479 3- (trifluoromethyl)- 5,6,7,8-tetrahydro-1,6- naphthyridine 2-[(2,4- dimethyl- benzyl)- methyl-amino]- hexahydro- pentalene-3a- carboxylic acid (C, A)

1.5 2.06 min (c) (M + H)⁺ 486

TABLE 2 Examples synthesized using general procedure C m/z or ¹H NMR (d6DMSO, HPLC R_(t) 400 Amine Core Product Ex. # (Method) MHz)(2,4-dimethyl- benzyl)- methylamine 3a-[4-(3- trifluorometh- yl-phenyl)-piperazine-1- carbonyl]- hexahydro- pentalen-2- one (A, B)

2.1 2.32 min (a) (M + H)⁺ 514 4-phenyl- piperidine 3a-[4-(3-trifluorometh- yl-phenyl)- piperazine-1- carbonyl]- hexahydro-pentalen-2- one (A, B)

2.2 2.29 min (a) (M + H)⁺ 526 4-phenyl- cyclohexyl- amine 3a-[4-(3-trifluorometh- yl-phenyl)- piperazine-1- carbonyl]- hexahydro-pentalen-2- one (A, B)

2.3 2.45 min (a) (M + H)⁺ 540 (tetrahydro- pyran-4-yl)- methylamine3a-[4-(3- trifluorometh- yl-phenyl)- piperazine-1- carbonyl]- hexahydro-pentalen-2- one (A, B)

2.4 1.89 min (a) (M + H)⁺ 480 2,3-dihydro- 1H-isoindole 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.5 1.78 min (a) (M + H)⁺ 456 4-fluoro- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.6 1.81 min (a) (M + H)⁺ 462 2-fluoro- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.7 1.77 min (a) (M + H)⁺ 462 4- aminomethyl- benzonitrile 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.8 1.75 min (a) (M + H)⁺ 469 indan-1-yl- amine 3a-(3- (trifluorometh-yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6- carbonyl)hexa- hydro-pentalen-2(1H)-one (A, B)

2.9 1.83 min (a) (M + H)⁺ 470 3,4-dimethyl- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.10 1.93 min (a) (M + H)⁺ 472 2,5-dimethyl- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.11 1.93 min (a) (M + H)⁺ 472 2-methoxy- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.12 1.83 min (a) (M + H)⁺ 474 3-methoxy- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.13 1.79 min (a) (M + H)⁺ 474 4-methoxy- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.14 1.85 min (a) (M + H)⁺ 474 3-chloro- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.15 1.93 min (a) (M + H)⁺ 478 4-chloro- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.16 1.9 min  (a) (M + H)⁺ 478 1,2,3,4- tetrahydro- naphthalen-1-ylamine 3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6-naphthyridine- 6- carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.17 1.96 min (a) (M + H)⁺ 484 (3- aminomethyl- phenyl)- dimethyl- amine3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.18 1.88 min (a) (M + H)⁺ 487 N-(4- aminomethyl- phenyl)- acetamide3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.19 1.61 min (a) (M + H)⁺ 501 3-pyrazol-1- yl- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.20 1.79 min (a) (M + H)⁺ 510 3- trifluoromethyl- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.21 2.22 min (a) (M + H)⁺ 512 2- trifluoromethyl- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.22 1.95 min (a) (M + H)⁺ 512 2,4-dichloro- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.23 1.99 min (a) (M + H)⁺ 512 3,4-dichloro- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.24 2.07 min (a) (M + H)⁺ 512 biphenyl-4-yl- methylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.25 2.08 min (a) (M + H)⁺ 520 2- trifluorometh- oxy- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.26 2.08 min (a) (M + H)⁺ 528 3-trifluoro- methoxy- benzylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.27 2.06 min (a) (M + H)⁺ 528 N-(4- aminomethyl- phenyl)- methanesulfonamide 3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6-naphthyridine- 6- carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.28 1.77 min (a) (M + H)⁺ 537 indan-2-yl- amine 3a-(3- (trifluorometh-yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6- carbonyl)hexa- hydro-pentalen-2(1H)-one (A, B)

2.29 1.86 min (a) (M + H)⁺ 470 2-o-tolyl- ethylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.30 1.94 min (a) (M + H)⁺ 472 2-p-tolyl- ethylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.31 1.94 min (a) (M + H)⁺ 472 2-m-tolyl- ethylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.32 1.94 min (a) (M + H)⁺ 472 4-(2-amino- ethyl)-phenol 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.33 1.69 min (a) (M + H)⁺ 474 2-(2,5- dimethyl- phenyl)- ethylamine3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.34 2.02 min (a) (M + H)⁺ 486 2-(2,4- dimethyl- phenyl)- ethylamine3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.35 2.06 min (a) (M + H)⁺ 486 2-(4- trifluoromethyl- phenyl)-ethylamine 3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6-naphthyridine- 6- carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.36 2.07 min (a) (M + H)⁺ 526 2-(3- trifluoromethyl- phenyl)-ethylamine 3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6-naphthyridine- 6- carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.37 2.03 min (a) (M + H)⁺ 526 2-(3,4- dichloro- phenyl)- ethylamine3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.38 2.05 min (a) (M + H)⁺ 526 2-biphenyl-2- yl-ethylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.39 2.17 min (a) (M + H)⁺ 534 2-biphenyl-4- yl-ethylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.40 2.13 min (a) (M + H)⁺ 534 (R)-1-phenyl-1- ethylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.41 1.87 min (a) (M + H)⁺ 458 (S)-1-phenyl-1- ethylamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.42 1.85 min (a) (M + H)⁺ 458 pyridin-2-yl- methanamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.43 1.62 min (c) (M + H)⁺ 445 2-(pyridin-2- yl)ethanamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.44 1.67 min (c) (M + H)⁺ 459 2-(pyridin-3- yl)ethanamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.45 1.57 min (c) (M + H)⁺ 459 (5- methylpyrazin- 2-yl)- methanamine3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.46 1.57 min (c) (M + H)⁺ 460 2-(thiophen-2- yl)ethanamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.47 1.79 min (c) (M + H)⁺ 464 1,1- dioxidotetra- hydrothien-3-yl- amine3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.48 1.60 min (c) (M + H)⁺ 472 Decahydroiso- quinoline 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.49 1.91 min (c) (M + H)⁺ 476 2-cyclohexyl- pyrrolidine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.50 2.02 min (c) (M + H)⁺ 490 4-(pyrrolidin- 1-yl)piperidine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.51 1.34 min (c) (M + H)⁺ 491 2-(1H-indol-3- yl)ethanamine 3a-(3-(trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.52 1.88 min (c) (M + H)⁺ 497 2-(1-methyl- 1H-indol-3- yl)ethanamine3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.53 2.00 min (c) (M + H)⁺ 511 piperidin-1- yl(piperidin-2- yl)methanone3a-(3- (trifluorometh- yl)-5,6,7,8- tetrahydro- 1,6- naphthyridine- 6-carbonyl)hexa- hydro- pentalen-2(1H)-one (A, B)

2.54 1.76 min (c) (M + H)⁺ 533

What is claimed is:
 1. A compound of Formula (I)

pharmaceutically acceptable salts, isomers thereof or stereoisomersthereof wherein R^(a) is H or optionally substituted (C₁-C₆)alkyl; R^(b)is selected from the optionally substituted group consisting of—(CH₂)_(n)-aryl, —CH(CH₃)-aryl, —(CH₂)_(n)-aryl-aryl,—(CH₂)_(n)-aryl-heteroaryl, —(CH₂)_(n)—(C₃-C₈)cycloalkyl,—(CH₂)_(n)-heteroaryl, —(CH₂)_(n)-heterocyclyl and—(C₃-C₈)cycloalkyl-aryl; or R^(a) and R^(b) are taken together with thenitrogen to form 2,3-dihydro-1H-isoindolyl, decahydroisoquinolinyl,optionally substituted piperidinyl or optionally substitutedpyrrolidinyl; Y is selected from the optionally substituted groupconsisting of 5,6,7,8-tetrahydro[1,6]naphthridinyl,—NH—(CH₂)_(n)-heterocyclyl wherein the NH is attached to the carbonyland -heterocyclyl-aryl wherein the heterocyclyl is attached to thecarbonyl; and n is 0, 1 or
 2. 2. The compound or salt according to claim1 wherein Y is selected from the optionally substituted group consistingof 5,6,7,8-tetrahydro[1,6]naphthridinyl, —NH—(CH₂)₂-pyrrolidinyl and-piperazinyl-phenyl.
 3. The compound or salt according to claim 2wherein R^(a) is H or methyl.
 4. The compound or salt according to claim3 wherein R^(b) is selected from the optionally substituted groupconsisting of —CH₂-phenyl, —CH₂-phenyl-phenyl, —(CH₂)₂-phenyl,—CH(CH₃)-phenyl, —CH₂CH₂-phenyl-phenyl, —CH₂-phenyl-pyrazolyl,phenyl-pyrazolyl, indanyl, —(CH₂)₂-indolyl, 1,2,3,4-tetrahydronaphthyl,—(CH₂)-pyrazinyl, —(CH₂)-pyridinyl, —(CH₂)₂-pyridinyl,—(CH₂)₂-pyrrolidinyl, —(CH₂)₂-thienyl, tetrahydrothienyl-1,1-dioxide,—(CH₂)₂-piperidinyl, tetrahydropyranyl and -cyclohexyl-phenyl.
 5. Thecompound or salt according to claim 4 wherein R^(b) is selected from theoptionally substituted group consisting of —CH₂-phenyl, —(CH₂)₂-phenyl,—CH₂-phenyl-pyrazolyl, indanyl, —(CH₂)-indolyl,1,2,3,4-tetrahydronaphthyl, —(CH₂)₂-pyridinyl and -cyclohexyl-phenyl. 6.The compound or salt according to claim 5 wherein Y is selected from theoptionally substituted group consisting of5,6,7,8-tetrahydro[1,6]naphthyridinyl and -piperazinyl-phenyl.
 7. Thecompound or salt according to claim 6 wherein R^(b) is selected from theoptionally substituted group consisting of —CH₂-phenyl, —(CH₂)₂-phenyl,1,2,3,4-tetrahydronaphthyl, —CH₂-phenyl-pyrazolyl, indanyl,—(CH₂)₂-pyridinyl and -cyclohexyl-phenyl.
 8. The compound or saltaccording to claim 7 wherein R^(b) is selected from the optionallysubstituted group consisting of —CH₂-phenyl, 1,2,3,4 tetrahydronaphthyland -cyclohexyl-phenyl.
 9. The compound or salt according to claim 8wherein R^(b) is optionally substituted with one or more substituentsselected from the group consisting of alkyl, alkoxy, halogen, CN, OH,CF₃, OCF₃, NH₂, NH(CH₃) and N(CH₃)₂.
 10. The compound or salt accordingto claim 9 wherein Y is optionally substituted with CF₃.
 11. Thecompound or salt according to claim 2 wherein R^(a) and R^(b) are takentogether with the nitrogen to form 2,3-dihydro-1H-isoindolyl, optionallysubstituted piperidinyl or optionally substituted pyrrolidinyl.
 12. Thecompound or salt according to claim 11 wherein the optionallysubstituted piperidinyl or optionally substituted pyrrolidinyl isoptionally substituted by substituents selected from the groupconsisting of optionally substituted cyclohexyl and optionallysubstituted phenyl.
 13. The compound or salt according to claim 12wherein Y is optionally substituted5,6,7,8-tetrahydro[1,6]naphthyridinyl.
 14. The compound or saltaccording to claim 13 wherein the optionally substituted piperidinyl issubstituted with optionally substituted phenyl or optionally substitutedpyrrolidinyl.
 15. The compound or salt according to claim 14 wherein theoptionally substituted piperidinyl is substituted with optionallysubstituted pyrrolidinyl.
 16. The compound or salt according to claim 14wherein the optionally substituted piperidinyl is substituted withoptionally substituted phenyl.
 17. The compound or salt according toclaim 12 wherein the optionally substituted pyrrolidinyl is substitutedby optionally substituted cyclohexyl.
 18. A pharmaceutical compositioncomprising a compound of Formula (I)

or a pharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient, wherein R^(a) is H or optionallysubstituted (C₁-C₆)alkyl; R^(b) is selected from the optionallysubstituted group consisting of —(CH₂)_(n)-aryl, —CH(CH₃)-aryl,—(CH₂)_(n)-aryl-aryl, —(CH₂)_(n)-aryl-heteroaryl,—(CH₂)_(n)—(C₃-C₈)cycloalkyl, —(CH₂)_(n)-heteroaryl,—(CH₂)_(n)-heterocyclyl and —(C₃-C₈)cycloalkyl-aryl; or R^(a) and R^(b)are taken together with the nitrogen to form 2,3-dihydro-1H-isoindolyl,decahydroisoquinolinyl, optionally substituted piperidinyl or optionallysubstituted pyrrolidinyl; Y is selected from the optionally substitutedgroup consisting of 5,6,7,8-tetrahydro[1,6]naphthyridinyl,—NH—(CH₂)_(n)-heterocyclyl wherein the NH is attached to the carbonyland -heterocyclyl-aryl wherein the heterocyclyl is attached to thecarbonyl; and n is 0, 1 or
 2. 19. The compound or salt according toclaim 1, wherein the compound is selected from the group consisting of:


20. A pharmaceutical composition comprising a compound of claim 19, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier or excipient.